ERBB2

Summary

ERBB2 (erb-b2 receptor tyrosine kinase 2, HGNC:3430) is a protein-coding gene on chromosome 17q12, encoding Receptor tyrosine-protein kinase erbB-2 (P04626). Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. In precision oncology, ERBB2 Amplification confers sensitivity to Trastuzumab in HER2 Positive Breast Cancer (CIViC Level A); 190 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 17.7% of cell lines).

This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.

Source: NCBI Gene 2064 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hirschsprung disease (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 836 total — 16 pathogenic, 10 likely-pathogenic (top 4% of genes corpus-wide)
• GTEx eGene: eQTL in 13 tissues, sQTL in 17 (q < 0.05)
• Phenotypes (HPO): 49
• Drug target: yes — 38 curated mechanism-of-action drugs, 6 via a complex or family; 83 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 12 — Afatinib Dimaleate, Dacomitinib, Lapatinib Ditosylate, +9 more
• Approved drugs acting on a complex or family including it: 2 — Vandetanib, Zenocutuzumab (Epidermal growth factor receptor; ErbB-2/ErbB-3 heterodimer)
• Precision-oncology evidence (CIViC): 191 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 16 cancer types (inferred from mutation patterns)
• Cancer dependency (DepMap): dependent in 17.7% of screened cell lines
• Constraint (gnomAD): pLI 0.06 (LoF-tolerant), LOEUF 0.52 (moderately constrained)
• MANE Select transcript: NM_004448
• Interaction hub: 6,884 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3430
Approved symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	NEU, HER-2, CD340, HER2, c-ERB2, c-ERB-2, MLN-19, p185(erbB2)
Ensembl gene	ENSG00000141736
Ensembl biotype	protein_coding
OMIM	164870
Entrez	2064

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 28 protein_coding, 13 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000269571

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 2: 4, TSL 3: 5, TSL 4: 2, TSL 5: 3

ENST00000269571, ENST00000445658, ENST00000578199, ENST00000578373, ENST00000578502, ENST00000578630, ENST00000578709, ENST00000580074, ENST00000582648, ENST00000582788, ENST00000582818, ENST00000583038, ENST00000583391, ENST00000584014, ENST00000584099, ENST00000584450, ENST00000584601, ENST00000584684, ENST00000584888, ENST00000584908, ENST00000863095, ENST00000863096, ENST00000863097, ENST00000863098, ENST00000863099, ENST00000863100, ENST00000863101, ENST00000863102, ENST00000863103, ENST00000938923, ENST00000938924, ENST00000938925, ENST00000959774, ENST00000959775, ENST00001005734, ENST00001018292, ENST00001018293, ENST00001018294, ENST00001066796, ENST00001066797, ENST00001066798, ENST00001066799, ENST00001066800, ENST00001066801, ENST00001066802, ENST00001066803, ENST00001066805, ENST00001116003, ENST00001141787

RefSeq mRNA: 30 — MANE Select: NM_004448 NM_001005862, NM_001289936, NM_001289937, NM_001289938, NM_001382782, NM_001382783, NM_001382784, NM_001382785, NM_001382786, NM_001382787, NM_001382788, NM_001382789, NM_001382790, NM_001382791, NM_001382792, NM_001382793, NM_001382794, NM_001382795, NM_001382796, NM_001382797, NM_001382798, NM_001382799, NM_001382800, NM_001382801, NM_001382802, NM_001382803, NM_001382804, NM_001382805, NM_001382806, NM_004448

CCDS: CCDS32642, CCDS45667, CCDS77016, CCDS77017, CCDS92296

Canonical transcript exons

ENST00000269571 — 27 exons

Exon	Start	End
ENSE00003465438	39726562	39726659
ENSE00003474439	39706990	39707141
ENSE00003523294	39715446	39715536
ENSE00003528993	39727295	39727547
ENSE00003530664	39715286	39715359
ENSE00003564965	39716301	39716433
ENSE00003572793	39711928	39712047
ENSE00003580476	39725327	39725402
ENSE00003585058	39726815	39727003
ENSE00003591380	39723319	39723457
ENSE00003605099	39710086	39710201
ENSE00003610105	39712322	39712448
ENSE00003625564	39715740	39715939
ENSE00003625600	39724726	39724911
ENSE00003629275	39723912	39724010
ENSE00003629888	39719787	39719834
ENSE00003632167	39717320	39717480
ENSE00003648452	39709318	39709452
ENSE00003650103	39725707	39725853
ENSE00003653182	39708321	39708534
ENSE00003655754	39723538	39723660
ENSE00003657083	39725049	39725204
ENSE00003663782	39709813	39709881
ENSE00003675634	39716515	39716605
ENSE00003679402	39710340	39710481
ENSE00003907546	39727689	39728658
ENSE00003909903	39700064	39700311

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 97.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8860 / max 788.7767, expressed in 1672 samples.

Highest expression (Bgee): lower esophagus mucosa, uterine tube, sural nerve, skin of leg, esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ERBB2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 17 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	sqtl	8.1e-23	+0.66	17:39723335:A:G
Skin Not Sun Exposed Suprapubic	sqtl	3.2e-22	+0.70	17:39723335:A:G
Artery Tibial	sqtl	4.0e-19	+0.68	17:39723335:A:G
Nerve Tibial	sqtl	4.3e-18	+0.65	17:39723335:A:G
Esophagus Mucosa	sqtl	5.0e-18	+0.68	17:39723335:A:G
Nerve Tibial	eqtl	9.7e-18	-0.22	17:39674782:A:G
Thyroid	sqtl	5.1e-15	+0.61	17:39723335:A:G
Skin Sun Exposed Lower leg	eqtl	6.5e-13	-0.11	17:39670910:A:G
Skin Not Sun Exposed Suprapubic	eqtl	9.1e-10	-0.13	17:39677314:G:C
Lung	sqtl	2.0e-08	+0.51	17:39723335:A:G
Heart Atrial Appendage	eqtl	2.1e-06	-0.15	17:39672243:T:C
Cells Cultured fibroblasts	sqtl	9.1e-06	+0.41	17:39723335:A:G
Colon Transverse	sqtl	1.1e-05	+0.53	17:39723335:A:G
Artery Aorta	sqtl	1.9e-04	+0.47	17:39723335:A:G
Heart Left Ventricle	eqtl	7.0e-04	-0.12	17:39668292:G:A
Esophagus Gastroesophageal Junction	sqtl	8.5e-04	+0.55	17:39723335:A:G
Artery Aorta	eqtl	7.9e-03	+0.43	17:40053224:C:G
Brain Spinal cord cervical c-1	sqtl	8.1e-03	-1.40	17:40563898:A:G
Breast Mammary Tissue	eqtl	1.1e-02	-0.15	17:39921497:T:C
Esophagus Muscularis	sqtl	1.4e-02	+0.42	17:39723335:A:G

FANTOM5 promoters

10 alternative TSS:

Promoter ID	TPM avg	Samples expressed
160623	9.9827	1303
160622	6.3473	1311
160621	3.9997	1212
160618	3.4329	1436
160619	0.5707	289
160620	0.2726	130
160626	0.1540	36
160627	0.1030	31
160624	0.0134	1
160625	0.0097	1

Top tissues by expression

showing 100 of 297 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.71	gold quality
right uterine tube	UBERON:0001302	97.26	gold quality
sural nerve	UBERON:0015488	96.73	gold quality
skin of leg	UBERON:0001511	96.65	gold quality
esophagus mucosa	UBERON:0002469	96.57	gold quality
metanephros cortex	UBERON:0010533	96.57	gold quality
skin of abdomen	UBERON:0001416	96.50	gold quality
nerve	UBERON:0001021	96.39	gold quality
tibial nerve	UBERON:0001323	96.39	gold quality
renal medulla	UBERON:0000362	96.35	gold quality
minor salivary gland	UBERON:0001830	96.10	gold quality
right lobe of thyroid gland	UBERON:0001119	96.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.02	gold quality
mucosa of transverse colon	UBERON:0004991	95.99	gold quality
left lobe of thyroid gland	UBERON:0001120	95.86	gold quality
zone of skin	UBERON:0000014	95.48	gold quality
descending thoracic aorta	UBERON:0002345	95.36	gold quality
thyroid gland	UBERON:0002046	95.30	gold quality
mouth mucosa	UBERON:0003729	95.08	gold quality
right atrium auricular region	UBERON:0006631	94.99	gold quality
saliva-secreting gland	UBERON:0001044	94.76	gold quality
transverse colon	UBERON:0001157	94.60	gold quality
rectum	UBERON:0001052	94.58	gold quality
thoracic aorta	UBERON:0001515	94.55	gold quality
ascending aorta	UBERON:0001496	94.45	gold quality
ventricular zone	UBERON:0003053	94.34	gold quality
adult mammalian kidney	UBERON:0000082	94.22	gold quality
aorta	UBERON:0000947	93.98	gold quality
epithelium of bronchus	UBERON:0002031	93.98	gold quality
apex of heart	UBERON:0002098	93.96	gold quality
pharyngeal mucosa	UBERON:0000355	93.90	gold quality
nipple	UBERON:0002030	93.85	gold quality
bronchus	UBERON:0002185	93.84	gold quality
right coronary artery	UBERON:0001625	93.83	gold quality
esophagus	UBERON:0001043	93.62	gold quality
popliteal artery	UBERON:0002250	93.57	gold quality
tibial artery	UBERON:0007610	93.54	gold quality
colonic epithelium	UBERON:0000397	93.51	gold quality
palpebral conjunctiva	UBERON:0001812	93.48	gold quality
bronchial epithelial cell	CL:0002328	93.43	gold quality
vagina	UBERON:0000996	93.35	gold quality
duodenum	UBERON:0002114	93.23	gold quality
gall bladder	UBERON:0002110	93.19	gold quality
cardiac atrium	UBERON:0002081	93.13	gold quality
small intestine	UBERON:0002108	93.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.00	gold quality
body of stomach	UBERON:0001161	92.92	gold quality
jejunal mucosa	UBERON:0000399	92.66	gold quality
endometrium epithelium	UBERON:0004811	92.62	gold quality
stomach	UBERON:0000945	92.60	gold quality
body of pancreas	UBERON:0001150	92.59	gold quality
oral cavity	UBERON:0000167	92.53	gold quality
coronary artery	UBERON:0001621	92.51	gold quality
left coronary artery	UBERON:0001626	92.51	gold quality
heart left ventricle	UBERON:0002084	92.38	gold quality
mammalian vulva	UBERON:0000997	92.36	gold quality
heart	UBERON:0000948	92.25	gold quality
upper leg skin	UBERON:0004262	92.22	gold quality
prostate gland	UBERON:0002367	92.20	gold quality
cardiac ventricle	UBERON:0002082	92.13	gold quality
trachea	UBERON:0003126	92.13	gold quality
intestine	UBERON:0000160	92.03	gold quality
ectocervix	UBERON:0012249	91.98	gold quality
urinary bladder	UBERON:0001255	91.82	gold quality
colon	UBERON:0001155	91.76	gold quality
large intestine	UBERON:0000059	91.67	gold quality
trigeminal ganglion	UBERON:0001675	91.67	gold quality
stromal cell of endometrium	CL:0002255	91.66	gold quality
penis	UBERON:0000989	91.50	gold quality
upper lobe of left lung	UBERON:0008952	91.39	gold quality
dorsal root ganglion	UBERON:0000044	91.28	gold quality
endocervix	UBERON:0000458	91.13	gold quality
upper lobe of lung	UBERON:0008948	90.97	gold quality
mucosa of stomach	UBERON:0001199	90.93	gold quality
right lung	UBERON:0002167	90.80	gold quality
urethra	UBERON:0000057	90.71	gold quality
fundus of stomach	UBERON:0001160	90.69	gold quality
tonsil	UBERON:0002372	90.55	gold quality
nasal cavity mucosa	UBERON:0001826	90.50	gold quality
seminal vesicle	UBERON:0000998	90.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.39	gold quality
body of uterus	UBERON:0009853	90.18	gold quality
lower esophagus	UBERON:0013473	90.17	gold quality
placenta	UBERON:0001987	90.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.15	gold quality
eye	UBERON:0000970	90.00	gold quality
kidney	UBERON:0002113	89.85	gold quality
corpus epididymis	UBERON:0004359	89.69	gold quality
mammary duct	UBERON:0001765	89.68	gold quality
fallopian tube	UBERON:0003889	89.46	gold quality
right ovary	UBERON:0002118	89.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.27	gold quality
uterine cervix	UBERON:0000002	89.24	gold quality
pylorus	UBERON:0001166	89.17	gold quality
left uterine tube	UBERON:0001303	89.14	gold quality
pancreas	UBERON:0001264	89.10	gold quality
left ovary	UBERON:0002119	89.08	gold quality
colonic mucosa	UBERON:0000317	89.04	gold quality
sigmoid colon	UBERON:0001159	89.03	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	159.22
E-MTAB-6678	yes	16.32
E-ANND-3	yes	9.97
E-CURD-112	yes	4.23
E-CURD-53	no	2882.67

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skin 1	tissue	84.8	medium
Esophagus	tissue	77.7	low
Parathyroid gland	tissue	76.8	low
Colon	tissue	63.8	not detected
Small intestine	tissue	63.4	low
Fallopian tube	tissue	60.4	medium
Duodenum	tissue	59.8	not detected
Kidney	tissue	56.1	low
Salivary gland	tissue	54.8	low
Breast	tissue	52.4	medium
Vagina	tissue	50.7	low
Seminal vesicle	tissue	47.5	low
Stomach 1	tissue	46.8	not detected
Prostate	tissue	46.0	low
Rectum	tissue	45.5	low
Heart muscle	tissue	44.5	medium
Thyroid gland	tissue	40.6	low
Choroid plexus	tissue	38.7
Urinary bladder	tissue	37.4	medium
Cervix	tissue	34.1	medium
Lung	tissue	34.1	medium
Gallbladder	tissue	29.0	not detected
Liver	tissue	28.4	low
Pancreas	tissue	26.1	not detected
Tonsil	tissue	26.1	low
Placenta	tissue	25.4	medium
Epididymis	tissue	25.1	not detected
Smooth muscle	tissue	23.3	not detected
Ovary	tissue	22.6	not detected
Skeletal muscle	tissue	19.5	medium
Endometrium 1	tissue	19.1	medium
Nucleus accumbens	tissue	19.1
Hippocampus	tissue	17.1	not detected
Pituitary gland	tissue	17.0
Locus coeruleus	tissue	16.3
Tongue	tissue	14.0
Spinal cord	tissue	13.8
Superior colliculi	tissue	13.7
Periaqueductal gray	tissue	12.9
Olfactory bulb	tissue	11.9
Hippocampal formation	tissue	11.7
Appendix	tissue	11.5	medium
Substantia nigra	tissue	11.3
Medulla oblongata	tissue	11.2
Adipose tissue	tissue	10.9	not detected
Amygdala	tissue	10.8
Hypothalamus	tissue	10.7
Basal ganglia	tissue	10.4	not detected
Thalamus	tissue	10.2
Cerebral cortex	tissue	10.1	not detected
Insular cortex	tissue	10.1
Cerebellum	tissue	9.7	not detected
Midbrain	tissue	9.4
Entorhinal cortex	tissue	9.3
Septum	tissue	9.3
Retrosplenial cortex	tissue	9.1
Temporal cortex	tissue	8.9
Corpus callosum	tissue	8.8
Pons	tissue	8.6
Ventral forebrain	tissue	8.6

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Blood vessel (53.9), Periaquaductal grey, lateral (38.3), Area postrema (37.7), Globus pallidus, externus (32.4), Periaquaductal grey, dorsal (31.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
MSI1	Activation
NOTCH3	Activation

Upstream regulators (CollecTRI, top): AR, ATF1, ATF4, ATF7, CREB1, DENND4A, DTX1, EGR2, ELF1, ELF3, ELK1, ENO1, EP300, ESR1, ESR2, ETS1, ETS2, ETV1, ETV4, FOXM1, FOXN1, FOXP3, GABPA, GATA3, GATA4, GATA5, GLI3, HIF1A, HNF4A, HSF1, JUN, JUND, MYB, MYBL2, MYC, NCOA1, NCOA2, NCOA3, NFE2L2, NFKB

miRNA regulators (miRDB)

Targeting ERBB2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 48 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Functional genomics

gnomAD constraint: pLI 0.0631, LOEUF 0.518, missense Z 4.25 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000269571 splits into 6 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:39,700,239–39,707,122	101 / 95.1	1.06	no
17:39,707,123–39,723,431	569 / 803.5	0.71	no
17:39,723,432–39,725,757	152 / 318.1	0.48	no
17:39,725,758–39,726,625	63 / 74.2	0.85	no
17:39,726,626–39,726,825	8 / 20.4	0.39	no
17:39,726,826–39,728,041	312 / 343.8	0.91	no
DepMap (CRISPR cell-line fitness): dependent in 17.7% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): MDA-MB-361 (-3.474), ESO26 (-3.035), OCUB-M (-2.668), SNU-308 (-2.638), MDA-MB-453 (-2.549), UACC-893 (-2.444), KYSE-410 (-2.415), AU565 (-2.293), NCC-CCS1B-C1 (-2.219), NCI-H2170 (-2.181), TGBC18TKB (-2.089), LN-229 (-1.981), HCC202 (-1.889), TE-4 (-1.889), SK-OV-3 (-1.824).

Literature-anchored findings (GeneRIF, showing 40)

• peptide library generation for HER2/neu ligand identification (PMID:11700053)
• HER-2 gene amplification and protein overexpression has been associated with increased risk of advanced-stage breast cancer and poor prognosis. (PMID:11731415)
• Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. (PMID:11751413)
• overexpression not associated with in vitro drug resistance to CMF or FEC chemotherapy combinations in primary breast cancer (PMID:11759828)
• Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer. (PMID:11786427)
• Identification of a minimal c-erbB-2 promoter region that mediates preferential expression of a linked foreign gene in human breast cancer cells (PMID:11836576)
• NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer (PMID:11839648)
• HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. (PMID:11839672)
• Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma (PMID:11839675)
• Automated electrorotation to reveal dielectric variations related to HER-2/neu overexpression in MCF-7 sublines (PMID:11839684)
• ErbB-2 demonstrates a strong tendency toward stable self-association of transmembrane domains identifiable as coexisting populations of peptides whose associations are thought to modulate signal transduction. (PMID:11841227)
• lack of amplification in nasopharyngeal neoplasms (PMID:11850071)
• feasibility of fluorescence in situ hybridization analysis of HER-2/neu amplification in oral mucosa brushings and to compare the HER-2/neu status with the history and smoking and drinking habits of healthy subjects (PMID:11850076)
• Data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain. (PMID:11850540)
• Except in a certain subset of cases, aneusomy 17 probably is not a significant factor for HER-2/neu protein expression or for clinical assessment of HER-2/neu status. (PMID:11850542)
• Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of the ErbB-2/HER-2 oncoprotein and c-jun and c-fos oncogenes (PMID:11891317)
• Increased c-erbB-2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumour metastasis. (PMID:11895493)
• expression of cyclooxygenase 2 in HE-2 positive breast cancer (PMID:11901151)
• Epidermal growth factor contains both positive and negative determinants for interaction with ErbB-2/ErbB-3 heterodimers (PMID:11914075)
• expression correlated with increased event-free and overall survival in high-grade osteosarcoma (PMID:11920494)
• ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas. (PMID:11950845)
• p53 mutational pathway may favor selection for ErbB2 gene amplification during tumor progression in breast cancer (PMID:11953857)
• Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta (PMID:11960991)
• Cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and Her-2/neu are expressed in ovarian cancer. (PMID:11972392)
• gene is essential in preventing dilated cardiomyopathy (PMID:11984589)
• overexpression seen in 16% of NSCLC tumors, most frequently in adenocarcinomas and large cell carcinomas (PMID:11986780)
• identification of a dimerization motif for ErbB homomeric association (PMID:12000754)
• ErbB2 activation of ESX gene expression (PMID:12032832)
• ErbB2 membrane RTK can confer resistance to taxol-induced apoptosis by directly phosphorylating Cdc2. (PMID:12049736)
• HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. (PMID:12060497)
• S-erbB-2 serum levels above 40 U/ml independently predicted unfavorable response to 2d-line hormone or chemotherapy in advanced metastatic breast cancer. 1st-line drugs may select for overexpression of erbB-2 genes and lesser response to 2d-line drugs. (PMID:12065844)
• Expression of c-erbB-2 in node negative breast cancer does not correlate with estrogen receptor status, predictors of hormone responsiveness, or PCNA expression (PMID:12088102)
• Role of the N-terminus of epidermal growth factor in binding studied by phage display. (PMID:12093292)
• Her-2/neu expression and gene amplification in gastrinomas is correlated with tumor biology, growth, and aggressiveness. (PMID:12097278)
• Overexpression of erbb2 increases expression of VEGF A, C and D in breast carcinoma (PMID:12115372)
• the expression of mitochondria-encoded COXII is HRG-responsive. The levels of ErbB2 expression are decisive for the diverse biological activities of HRG. (PMID:12115729)
• ERBB2 binds to the SH2 domain of CHK and inhibits cell growth in human breast tumor cell lines (PMID:12122014)
• The expression of this molecule and its correlation with prognostic markers in patients with head and neck tumors (PMID:12127695)
• ErbB1 and ErbB2 employ different mechanisms of plasma membrane targeting during keratinocyte differentiation; cytoskeletal association may facilitate the coupling of activated ErbB1 and ERK. (PMID:12135609)
• ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. (PMID:12143054)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	erbb2	ENSDARG00000026294
mus_musculus	Erbb2	ENSMUSG00000062312
rattus_norvegicus	Erbb2	ENSRNOG00000006450

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715), RET (ENSG00000165731), AXL (ENSG00000167601), ROR2 (ENSG00000169071), ALK (ENSG00000171094), INSR (ENSG00000171105), ERBB4 (ENSG00000178568), CSF1R (ENSG00000182578), EPHB3 (ENSG00000182580), EPHA10 (ENSG00000183317), ROR1 (ENSG00000185483), EPHB4 (ENSG00000196411), NTRK1 (ENSG00000198400), DDR1 (ENSG00000204580)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95410) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 84 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality during organogenesis, complete penetrance	6
absent trabeculae carneae	3
premature death	3
increased mammary gland tumor incidence	3
embryonic lethality, complete penetrance	3
enlarged heart	2
abnormal myocardial fiber morphology	2
thin ventricular wall	2
absent myocardial trabeculae	2
abnormal sensory neuron innervation pattern	2
abnormal sympathetic ganglion morphology	2
abnormal glossopharyngeal nerve morphology	2
abnormal vagus nerve morphology	2
abnormal cranial ganglia morphology	2
abnormal geniculate ganglion morphology	2
abnormal trigeminal ganglion morphology	2
abnormal gait	2
irregular heartbeat	2
hemorrhage	2
abnormal blood circulation	2
dilated cardiomyopathy	2
abnormal ventral spinal root morphology	2
decreased heart ventricle muscle contractility	2
abnormal paravertebral ganglion morphology	2
decreased heart left ventricle muscle contractility	2

+59 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	P13387	100.0%	Diamond
Macaca mulatta	P55245	99.3%	Diamond
Pongo abelii	Q5RB22	98.0%	Diamond
Sus scrofa	Q00655	93.0%	Diamond
Bos taurus	Q17R13	93.0%	Diamond
Canis lupus familiaris	O18735	91.8%	Diamond
Mesocricetus auratus	Q60553	90.3%	Diamond
Xiphophorus maculatus	P13388	61.6%	Diamond
Drosophila melanogaster	Q9VZI2	55.7%	Diamond
Apis mellifera	P0CY46	51.9%	Diamond
Hydra vulgaris	P53356	47.2%	Diamond
Caenorhabditis elegans	G5EBZ8	43.1%	Diamond
Avian leukosis virus	P00534	100.0%	Diamond
Avian erythroblastosis virus (strain ts167)	P11273	100.0%	Diamond
Avian erythroblastosis virus (strain ES4)	P00535	99.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ZPBP2	protein-coding	124626
IKZF3	protein-coding	22806
GRB7	protein-coding	2886
MIEN1	protein-coding	84299
PNMT	protein-coding	5409
PGAP3	protein-coding	93210
MIR4728	ncRNA	100616132
TCAP	protein-coding	8557
STARD3	protein-coding	10948
GSDMB	protein-coding	55876

Protein

Protein identifiers

Receptor tyrosine-protein kinase erbB-2 — P04626 (reviewed: P04626)

Alternative names: Metastatic lymph node gene 19 protein, Proto-oncogene Neu, Proto-oncogene c-ErbB-2, Tyrosine kinase-type cell surface receptor HER2, p185erbB2

All UniProt accessions (11): B4DTR1, P04626, F5H1T4, J3KRI9, J3KTI5, J3QL83, J3QLU9, J3QLV2, J3QRJ7, J3QRX1, X5DNK3

UniProt curated annotations — full annotation on UniProt →

Function. Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. In the nucleus is involved in transcriptional regulation. Associates with the 5’-TCAAATTC-3’ sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.

Subunit / interactions. Homodimer. Heterodimer with EGFR, ERBB3 and ERBB4. Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196. Interacts with PLXNB1. Interacts (when phosphorylated on Tyr-1248) with MEMO1. Interacts with MUC1; the interaction is enhanced by heregulin (HRG). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain). Interacts (when phosphorylated on Tyr-1248) with ERBIN. Interacts with KPNB1, RANBP2, EEA1, CRM1 and CLTC. Interacts with PTK6. Interacts with RPA194 and ACTB. Interacts with PRKCABP, SRC and MYOC. Interacts (preferentially with the tyrosine phosphorylated form) with CPNE3; this interaction occurs at the cell membrane and is increased in a growth factor heregulin-dependent manner. Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with SORL1; this interaction regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulates ERBB2-mediated signaling. Interacts with SH3BGRL. Interacts with ROR1.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane Cell membrane. Early endosome. Cytoplasm. Perinuclear region. Nucleus Cytoplasm. Nucleus.

Tissue specificity. Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.

Post-translational modifications. Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligand-binding increases phosphorylation on tyrosine residues. Signaling via SEMA4C promotes phosphorylation at Tyr-1248. Dephosphorylated by PTPN12.

Disease relevance. Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The gene represented in this entry is involved in disease pathogenesis. Ovarian cancer (OC) [MIM:167000] The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. The gene represented in this entry is involved in disease pathogenesis. Lung cancer (LNCR) [MIM:211980] A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The gene represented in this entry is involved in disease pathogenesis. Gastric cancer (GASC) [MIM:613659] A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. The protein represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. Visceral neuropathy, familial, 2, autosomal recessive (VSCN2) [MIM:619465] An autosomal recessive disorder characterized by intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Patients also show peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, and sensorineural hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity.

Polymorphism. There are four alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012.

Miscellaneous. Produced by alternative initiation at Met-611 of isoform 1. Produced by alternative initiation at Met-687 of isoform 1. Produced by alternative splicing of isoform 1.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
P04626-1	1, ERBB2, HER2	yes
P04626-2	2, CTF-611
P04626-3	3, CTF-687
P04626-4	4
P04626-5	5
P04626-6	6, B

RefSeq proteins (30): NP_001005862, NP_001276865, NP_001276866, NP_001276867, NP_001369711, NP_001369712, NP_001369713, NP_001369714, NP_001369715, NP_001369716, NP_001369717, NP_001369718, NP_001369719, NP_001369720, NP_001369721, NP_001369722, NP_001369723, NP_001369724, NP_001369725, NP_001369726, NP_001369727, NP_001369728, NP_001369729, NP_001369730, NP_001369731, NP_001369732, NP_001369733, NP_001369734, NP_001369735, NP_004439* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000494	Rcpt_L-dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR006211	Furin-like_Cys-rich_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR008266	Tyr_kinase_AS	Active_site
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016245	Tyr_kinase_EGF/ERB/XmrK_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR032778	GF_recep_IV	Domain
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR049328	TM_ErbB1	Domain
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF14843, PF21314

Enzyme classification (BRENDA)

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (208 total): strand 63, helix 50, disulfide bond 25, sequence variant 13, modified residue 12, turn 11, glycosylation site 7, splice variant 7, mutagenesis site 5, region of interest 4, binding site 2, topological domain 2, signal peptide 1, chain 1, short sequence motif 1, compositionally biased region 1, active site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

showing 30 of 63 structures by resolution:

PDB	Title	Method	Resolution (Å)
1MFG	The Structure of ERBIN PDZ domain bound to the Carboxy-terminal tail of the ErbB2 Receptor	X-RAY DIFFRACTION	1.25
8VB5	Crystal structure of kinase domain of HER2 Exon 20 insertion mutant in complex with …	X-RAY DIFFRACTION	1.48
8JYR	Crystal structure of anti-HER2 antibody H2Mab-119 in complex with HER2 domain I	X-RAY DIFFRACTION	1.69
8U8X	crystal structure of the receptor tyrosine kinase Human HER2 (ERBB2) YVMA mutant kinase …	X-RAY DIFFRACTION	1.69
8JYQ	Crystal structure of cancer-specific anti-HER2 antibody H2Mab-214 in complex with epitope …	X-RAY DIFFRACTION	1.75
7PCD	HER2 IN COMPLEX WITH A COVALENT INHIBITOR	X-RAY DIFFRACTION	1.77
5TQS	Phospholipase C gamma-1 C-terminal SH2 domain bound to a phosphopeptide derived from the …	X-RAY DIFFRACTION	1.88
1MFL	The Structure of ERBIN PDZ domain bound to the Carboxy-terminal tail of the ErbB2 Receptor	X-RAY DIFFRACTION	1.88
4GFU	PTPN18 in complex with HER2-pY1248 phosphor-peptides	X-RAY DIFFRACTION	2
6LBX	Crystal structure of HER2 Domain IV and Rb-H2	X-RAY DIFFRACTION	2.03
9IUT	Crystal structure of cancer-specific anti-HER2 antibody H2Mab-250 in complex with epitope …	X-RAY DIFFRACTION	2.09
5MY6	Crystal structure of a HER2-Nb complex	X-RAY DIFFRACTION	2.25
3PP0	Crystal Structure of the Kinase domain of Human HER2 (erbB2).	X-RAY DIFFRACTION	2.25
1QR1	POOR BINDING OF A HER-2/NEU EPITOPE (GP2) TO HLA-A2.1 IS DUE TO A LACK OF INTERACTIONS IN …	X-RAY DIFFRACTION	2.4
3H3B	Crystal structure of the single-chain Fv (scFv) fragment of an anti-ErbB2 antibody chA21 …	X-RAY DIFFRACTION	2.45
2A91	Crystal structure of ErbB2 domains 1-3	X-RAY DIFFRACTION	2.5
4NND	Structural basis of PTPN18 fingerprint on distinct HER2 tyrosine phosphorylation sites	X-RAY DIFFRACTION	2.5
1N8Z	Crystal structure of extracellular domain of human HER2 complexed with Herceptin Fab	X-RAY DIFFRACTION	2.52
4HRL	Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via …	X-RAY DIFFRACTION	2.55
8VQD	HER2 S310F in complex with TL1 Fab	ELECTRON MICROSCOPY	2.61
4HRN	Structural Basis for Eliciting a Cytotoxic Effect in HER2-Overexpressing Cancer Cells via …	X-RAY DIFFRACTION	2.65
9MTE	CryoEM structure of extracellular domain of human HER2 complexed with two nano-bodies …	ELECTRON MICROSCOPY	2.66
8VQE	Homodimeric structure of HER2 S310F extracellular region	ELECTRON MICROSCOPY	2.67
6BGT	Structure of Trastuzumab Fab mutant in complex with Her2 extracellular domain	X-RAY DIFFRACTION	2.7
3BE1	Dual specific bH1 Fab in complex with the extracellular domain of HER2/ErbB-2	X-RAY DIFFRACTION	2.9
3MZW	HER2 extracelluar region with affinity matured 3-helix affibody ZHER2:342	X-RAY DIFFRACTION	2.9
6J71	HuA21-scFv in complex with the extracellular domain(ECD) of HER2	X-RAY DIFFRACTION	2.92
7MN5	Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain	ELECTRON MICROSCOPY	2.93
5O4G	HER2 in complex with Fab MF3958	X-RAY DIFFRACTION	3
9L1S	Structure of the HER2 (S310F) - pertuzumab (T30S/D31A) complex	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04626-F1	74.65	0.43

Antibody-complex structures (SAbDab)

27 antibodies co-crystallized with this protein: 1N8Z, 1S78, 3BE1, 3H3B, 3N85, 3WLW, 3WSQ, 5MY6, 5O4G, 6ATT, 6BGT, 6J71, 6OGE, 7MN8, 7QVK, 8JYQ, 8JYR, 8PWH, 8Q6J, 8VQD, 9IUT, 9L1S, 9MTE, 9MTX, ANBENITAMAB (+2 more)

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, CD markers, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, FDA approved drug targets, Biotech drugs, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; cytosol; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
845	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
726–734	ATP
753	ATP

Post-translational modifications (12)

Type	Positions
Phosphothreonine	182, 1166
Phosphotyrosine	877, 1112, 1139, 1196, 1248
Phosphoserine	1054, 1078, 1083, 1107, 1151

Disulfide bonds (25)

Type	Positions
Disulfide bond	26–53, 162–192, 195–204, 199–212, 220–227, 224–235, 236–244, 240–252, 255–264, 268–295, 299–311, 315–331, 334–338, 342–367, 475–504, 511–520, 515–528, 531–540, 544–560, 563–576, 567–584, 587–596, 600–623, 626–634, 630–642

Glycosylation sites (7)

Type	Positions
N-linked (glcnac…) asparagine	68, 124, 187, 259, 530, 571, 629

Mutagenesis-validated functional residues (5)

Position	Phenotype
317–318	reduces dimerization with erbb3.
611	prevents synthesis of isoform 2.
687	prevents synthesis of isoform 3.
706	no effect on isoform production.
712	no effect on isoform production.

Function

Pathways and Gene Ontology

Reactome pathways

30 curated (TAS) of 58; 19 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

58 pathways:

ID	Pathway	Evidence
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer ⚕	curated
R-HSA-9634285	Constitutive Signaling by Overexpressed ERBB2 ⚕	curated
R-HSA-9665737	Drug resistance in ERBB2 TMD/JMD mutants ⚕	curated
R-HSA-9665250	Resistance of ERBB2 KD mutants to AEE788 ⚕	curated
R-HSA-9665249	Resistance of ERBB2 KD mutants to afatinib ⚕	curated
R-HSA-9665251	Resistance of ERBB2 KD mutants to lapatinib ⚕	curated
R-HSA-9665246	Resistance of ERBB2 KD mutants to neratinib ⚕	curated
R-HSA-9665247	Resistance of ERBB2 KD mutants to osimertinib ⚕	curated
R-HSA-9665244	Resistance of ERBB2 KD mutants to sapitinib ⚕	curated
R-HSA-9665245	Resistance of ERBB2 KD mutants to tesevatinib ⚕	curated
R-HSA-9665233	Resistance of ERBB2 KD mutants to trastuzumab ⚕	curated
R-HSA-9665348	Signaling by ERBB2 ECD mutants ⚕	curated
R-HSA-9664565	Signaling by ERBB2 KD Mutants ⚕	curated
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants ⚕	curated
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells	curated
R-HSA-9927432	Developmental Lineage of Mammary Gland Myoepithelial Cells	curated
R-HSA-9938206	Developmental Lineage of Mammary Stem Cells	curated
R-HSA-8863795	Downregulation of ERBB2 signaling	curated
R-HSA-1358803	Downregulation of ERBB2:ERBB3 signaling	curated
R-HSA-9652282	Drug-mediated inhibition of ERBB2 signaling	curated
R-HSA-8847993	ERBB2 Activates PTK6 Signaling	curated
R-HSA-6785631	ERBB2 Regulates Cell Motility	curated
R-HSA-1306955	GRB7 events in ERBB2 signaling	curated
R-HSA-1963642	PI3K events in ERBB2 signaling	curated
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	curated
R-HSA-1257604	PIP3 activates AKT signaling	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse	curated
R-HSA-1227986	Signaling by ERBB2	curated
R-HSA-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-9665230	Drug resistance in ERBB2 KD mutants ⚕	—
R-HSA-2219528	PI3K/AKT Signaling in Cancer ⚕	—
R-HSA-1227990	Signaling by ERBB2 in Cancer ⚕	—
R-HSA-422475	Axon guidance	—
R-HSA-1266738	Developmental Biology	—
R-HSA-9734767	Developmental Cell Lineages	—
R-HSA-9734779	Developmental Cell Lineages of the Integumentary System	—
R-HSA-9924644	Developmental Lineages of the Mammary Gland	—
R-HSA-1963640	GRB2 events in ERBB2 signaling	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-199418	Negative regulation of the PI3K/AKT network	—
R-HSA-9675108	Nervous system development	—
R-HSA-1251932	PLCG1 events in ERBB2 signaling	electronic
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-1250196	SHC1 events in ERBB2 signaling	electronic
R-HSA-400685	Sema4D in semaphorin signaling	—
R-HSA-373755	Semaphorin interactions	—
R-HSA-162582	Signal Transduction	—
R-HSA-9006927	Signaling by Non-Receptor Tyrosine Kinases	—
R-HSA-8848021	Signaling by PTK6	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-8864260	Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (41): DNA-templated transcription (GO:0006351), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), enzyme-linked receptor protein signaling pathway (GO:0007167), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), cell population proliferation (GO:0008283), Schwann cell development (GO:0014044), peptidyl-tyrosine phosphorylation (GO:0018108), neuron differentiation (GO:0030182), positive regulation of cell growth (GO:0030307), regulation of microtubule-based process (GO:0032886), positive regulation of Rho protein signal transduction (GO:0035025), intracellular signal transduction (GO:0035556), ERBB2-ERBB3 signaling pathway (GO:0038133), ERBB2-EGFR signaling pathway (GO:0038134), ERBB2-ERBB4 signaling pathway (GO:0038135), wound healing (GO:0042060), negative regulation of apoptotic process (GO:0043066), positive regulation of MAP kinase activity (GO:0043406), positive regulation of MAPK cascade (GO:0043410), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), positive regulation of translation (GO:0045727), regulation of angiogenesis (GO:0045765), positive regulation of cell adhesion (GO:0045785), positive regulation of transcription by RNA polymerase I (GO:0045943), positive regulation of JNK cascade (GO:0046330), positive regulation of epithelial cell proliferation (GO:0050679), regulation of ERK1 and ERK2 cascade (GO:0070372), cellular response to growth factor stimulus (GO:0071363), cellular response to epidermal growth factor stimulus (GO:0071364), semaphorin-plexin signaling pathway (GO:0071526), positive regulation of protein targeting to membrane (GO:0090314), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), ERBB signaling pathway (GO:0038127), ERBB2 signaling pathway (GO:0038128), regulation of cell population proliferation (GO:0042127), cell development (GO:0048468), regulation of developmental process (GO:0050793), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (17): RNA polymerase I core binding (GO:0001042), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), transmembrane signaling receptor activity (GO:0004888), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), coreceptor activity (GO:0015026), receptor tyrosine kinase binding (GO:0030971), identical protein binding (GO:0042802), ErbB-3 class receptor binding (GO:0043125), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), growth factor binding (GO:0019838)

GO Cellular Component (23): semaphorin receptor complex (GO:0002116), nucleus (GO:0005634), nucleoplasm (GO:0005654), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), endosome membrane (GO:0010008), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), neuromuscular junction (GO:0031594), ruffle membrane (GO:0032587), ERBB3:ERBB2 complex (GO:0038143), presynaptic membrane (GO:0042734), myelin sheath (GO:0043209), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), cell periphery (GO:0071944)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Signaling by ERBB2	9
Signaling by ERBB2 in Cancer	2
Signaling by Receptor Tyrosine Kinases	1
Intracellular signaling by second messengers	1
Downregulation of ERBB2 signaling	1
PI3K/AKT Signaling in Cancer	1
Sema4D in semaphorin signaling	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Drug resistance in ERBB2 KD mutants	1

GO top-level categories

showing 60 of 79 GO namespaces:

Category	Terms
cellular anatomical structure	6
ERBB2 signaling pathway	3
protein binding	3
plasma membrane region	3
cellular process	2
regulation of cellular process	2
signal transduction	2
intracellular anatomical structure	2
signaling receptor activity	2
signaling receptor binding	2
endosome	2
cytoplasm	2
synaptic membrane	2
gene expression	1
RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
cell communication	1
signaling	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
enzyme-linked receptor protein signaling pathway	1
ERBB signaling pathway	1
Schwann cell differentiation	1
glial cell development	1
protein phosphorylation	1
cell differentiation	1
generation of neurons	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
microtubule-based process	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
ERBB3 signaling pathway	1
epidermal growth factor receptor signaling pathway	1
ERBB4 signaling pathway	1
response to wounding	1
tissue regeneration	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
RNA polymerase core enzyme binding	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein tyrosine kinase binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 37 of 81 annotations. The rest are phylogenetic / computational / electronic (IEA).

37 experimentally-supported GO terms:

GO term	NS	Evidence
ERBB2-EGFR signaling pathway	BP	direct assay
cell population proliferation	BP	direct assay
cell surface receptor protein tyrosine kinase signaling pathway	BP	direct assay
cell surface receptor signaling pathway	BP	direct assay
cellular response to epidermal growth factor stimulus	BP	mutant phenotype
cellular response to growth factor stimulus	BP	direct assay
intracellular signal transduction	BP	direct assay
peptidyl-tyrosine phosphorylation	BP	direct assay
phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	direct assay
positive regulation of MAP kinase activity	BP	direct assay
positive regulation of cell adhesion	BP	direct assay
positive regulation of cell growth	BP	mutant phenotype
positive regulation of epithelial cell proliferation	BP	direct assay
positive regulation of protein targeting to membrane	BP	direct assay
positive regulation of transcription by RNA polymerase I	BP	mutant phenotype
positive regulation of translation	BP	mutant phenotype
regulation of ERK1 and ERK2 cascade	BP	mutant phenotype
regulation of microtubule-based process	BP	direct assay
signal transduction	BP	direct assay
wound healing	BP	direct assay
ERBB3:ERBB2 complex	CC	direct assay
basolateral plasma membrane	CC	direct assay
cytosol	CC	direct assay
endosome membrane	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	direct assay
ErbB-3 class receptor binding	MF	physical interaction
RNA polymerase I core binding	MF	direct assay
identical protein binding	MF	physical interaction
protein heterodimerization activity	MF	physical interaction
protein tyrosine kinase activity	MF	direct assay
receptor tyrosine kinase binding	MF	physical interaction
signaling receptor binding	MF	physical interaction
transmembrane receptor protein tyrosine kinase activity	MF	direct assay
transmembrane signaling receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 6,884 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERBB2	ESR1	P03372	965
ERBB2	PGR	P06401	958
ERBB2	PIK3CA	P42336	924
ERBB2	BRCA1	P38398	923
ERBB2	KRAS	P01116	920
ERBB2	TP53	P04637	919
ERBB2	EGF	P01133	905
ERBB2	NRG1	P98202	896
ERBB2	PTEN	P60484	866
ERBB2	BRCA2	P51587	859
ERBB2	PIK3CG	P48736	856
ERBB2	CD274	Q9NZQ7	856
ERBB2	PIK3CB	P42338	855
ERBB2	MYC	P01106	854
ERBB2	CCND1	P24385	843

IntAct

Human interaction partners of ERBB2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 381 partners by confidence:

Partner	Interaction type	MIscore	Records
ERBB3	physical association	0.970	26
EGFR	association	0.950	20
GRB2	physical association	0.920	5
HSP90AA1	physical association	0.860	4
SHC1	physical association	0.820	12
ERBB4	physical association	0.820	4
HSP90AB1	physical association	0.790	4
STAT3	association	0.780	6
GRB7	direct interaction	0.780	5
PIK3R1	direct interaction	0.760	6
LRIG1	physical association	0.750	6
SRC	association	0.710	9
PIK3R2	direct interaction	0.700	7
CDC37	physical association	0.690	1
PTPN11	physical association	0.680	4
ERRFI1	physical association	0.660	1
HSPA5	physical association	0.660	1
ACTB	physical association	0.650	9
PTK6	physical association	0.630	4
PTPN3	direct interaction	0.620	2
EFNB1	physical association	0.600	11
IQGAP1	direct interaction	0.600	5
PIK3R3	direct interaction	0.590	9
RASA1	direct interaction	0.590	8
MAPK8IP1	physical association	0.590	4
PTPN12	physical association	0.590	4
JAK1	direct interaction	0.590	2
LRRC7	physical association	0.590	2
MATK	direct interaction	0.590	2
POLR1A	association	0.570	16

BioGRID (1,216 interactions; top human partners by supporting records in a sample of 600 records): EGFR (Co-localization; 23 records), ERBB3 (Co-localization; 15 records), ERBB2IP (Affinity Capture-Western; 11 records), SHC1 (Two-hybrid; 8 records), GRB2 (Affinity Capture-MS; 7 records), SRC (Negative Genetic; 7 records), CTNNB1 (Affinity Capture-Western; 6 records), BECN1 (Affinity Capture-Western; 5 records), HSP90AA1 (Affinity Capture-Western; 5 records), ABL1 (Reconstituted Complex; 4 records), DOCK7 (Biochemical Activity; 4 records), ERBB4 (Two-hybrid; 4 records), GRB7 (Affinity Capture-Western; 4 records), PTPN11 (Two-hybrid; 4 records), ABL2 (Reconstituted Complex; 3 records)

SIGNOR signaling

showing 45 of 99 signaling interactions:

A	Effect	B	Mechanism
EGF	up-regulates	ERBB2	binding
EGFR	up-regulates	ERBB2	binding
ERBB2	up-regulates	GRB2	relocalization
ERBB2	up-regulates	ERBB2	phosphorylation
ERBB2	up-regulates	ESR1	phosphorylation
LRIG1	down-regulates	ERBB2	ubiquitination
DTX1	“up-regulates quantity by expression”	ERBB2	“transcriptional regulation”
NOTCH1	“up-regulates quantity by expression”	ERBB2	“transcriptional regulation”
ERBB2	up-regulates	SHC3	relocalization
ERBB2	up-regulates	EGFR	binding
sapitinib	down-regulates	ERBB2	“chemical inhibition”
ERBB2	“up-regulates quantity by expression”	MSI1	“transcriptional regulation”
ERBB2	“up-regulates quantity by expression”	NOTCH3	“transcriptional regulation”
lapatinib	down-regulates	ERBB2	“chemical inhibition”
ERBB2	up-regulates	DOCK7	phosphorylation
PRKACA	up-regulates	ERBB2	phosphorylation
6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	down-regulates	ERBB2	“chemical inhibition”
afatinib	down-regulates	ERBB2	“chemical inhibition”
Arry-380	down-regulates	ERBB2	“chemical inhibition”
VARLITINIB	down-regulates	ERBB2	“chemical inhibition”
AV412	down-regulates	ERBB2	“chemical inhibition”
873837-23-1	down-regulates	ERBB2	“chemical inhibition”
canertinib	down-regulates	ERBB2	“chemical inhibition”
2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide	down-regulates	ERBB2	“chemical inhibition”
CUDC-101	down-regulates	ERBB2	“chemical inhibition”
Mubritinib	down-regulates	ERBB2	“chemical inhibition”
neratinib	down-regulates	ERBB2	“chemical inhibition”
XL-647	down-regulates	ERBB2	“chemical inhibition”
dacomitinib	down-regulates	ERBB2	“chemical inhibition”
LRIG1	down-regulates	ERBB2
LRIG3	up-regulates	ERBB2
ERBB2	up-regulates	PLCG1	binding
ERBB2	down-regulates	ERBB2	phosphorylation
DUSP3	“down-regulates activity”	ERBB2	dephosphorylation
EGFR	“up-regulates activity”	ERBB2	phosphorylation
ERBB2	“up-regulates activity”	ERBB2	phosphorylation
ADAM10	“up-regulates activity”	ERBB2	cleavage
“ado-trastuzumab emtansine”	“down-regulates activity”	ERBB2	binding
pertuzumab	“down-regulates activity”	ERBB2	binding
trastuzumab	“down-regulates activity”	ERBB2	binding
PTPN18	“down-regulates quantity by destabilization”	ERBB2	dephosphorylation
NRG1	up-regulates	ERBB2	binding
ERBB2	“down-regulates quantity by destabilization”	BBC3	phosphorylation
PTPRO	“down-regulates quantity by destabilization”	ERBB2	dephosphorylation
PTPN12	“down-regulates activity”	ERBB2	dephosphorylation

Protein complexes (CORUM) (13)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

13 complexes by size:

Complex	Subunits	Members
★ EGFR-ERBB2-PIK3C2A-PIK3C2B complex	4	ERBB2, PIK3C2A, PIK3C2B, EGFR
★ CD44-ERBB2-GRB2-VAV2 complex	4	CD44, ERBB2, GRB2, VAV2
★ EGF-EGFR-ERBB2 complex	3	EGF, EGFR, ERBB2
★ ERBB2-ERBB3-NRG1 complex	3	NRG1, ERBB2, ERBB3
★ ERBB2-ERBB4-NRG1 complex	3	NRG1, ERBB2, ERBB4
★ ERBB2-PGR-STAT3 complex	3	PGR, STAT3, ERBB2
★ BTC-ERBB2-ERBB4 complex	3	BTC, ERBB2, ERBB4
★ ERBB2-MEMO-SHC complex	3	ERBB2, MEMO1, SHC1
★ EPHA2-ERRB2 complex	2	EPHA2, ERBB2
★ ERBB2-MET complex	2	ERBB2, MET
★ ERBB2-L1CAM complex	2	ERBB2, L1CAM
★ ERBB2-GDF15 complex	2	ERBB2, GDF15
★ ERBB2 homodimer	1	ERBB2

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
HBEGF	receptor	Signaling by Epidermal growth factor

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 381 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by EGFRvIII	8	20.5×	8e-08
Regulation of signaling by CBL	11	19.6×	2e-10
Signaling by ERBB2 ECD mutants	8	19.3×	1e-07
Signaling by ERBB2 TMD/JMD mutants	11	18.8×	3e-10
Signaling by ERBB2 KD Mutants	12	18.2×	7e-11
GAB1 signalosome	8	18.2×	2e-07
Negative regulation of FLT3	7	17.9×	2e-06
Signaling by SCF-KIT	20	17.8×	1e-17

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine dephosphorylation	8	19.5×	6e-07
Fc-gamma receptor signaling pathway involved in phagocytosis	9	17.4×	2e-07
epidermal growth factor receptor signaling pathway	25	17.0×	3e-21
establishment or maintenance of epithelial cell apical/basal polarity	10	16.0×	1e-07
interleukin-6-mediated signaling pathway	5	15.4×	7e-04
B cell receptor signaling pathway	13	14.3×	2e-09
Fc-epsilon receptor signaling pathway	7	14.1×	4e-05
protein localization to synapse	6	12.6×	4e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ERBB2, commonly referred to as HER2, is amplified and/or overexpressed in 20-30% of invasive breast carcinomas. HER2-positive breast cancer is treated in a separate manner from other subtypes of breast cancer and commonly presents as more aggressive disease. Metastatic HER2-positive breast cancer is now commonly treated with HER2-targeted therapy. Apart from being amplified/overexpressed, ERBB2 activating mutations have been shown to have clinical importance in HER2-negative breast cancer. These mutations have shown sensitivity to the tyrosine kinase inhibitor neratinib, and highlight the importance of clinical sequencing efforts in treating breast cancer.

From intOGen — cancer-driver classification: activating (oncogene-like) across 16 cancer types — BLCA, BRCA, CESC, CHOL, COADREAD, EGC, ESCA, ESCC, LMS, LUAD, NSCLC, OVT…(+4 more).

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for ERBB2: 836 ClinVar records (26 pathogenic / likely pathogenic); 47 CIViC cancer variants; 2 PharmGKB clinical annotations; 17 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

836 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	10
Uncertain significance	386
Likely benign	329
Benign	30

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 26 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
44992	NM_004448.4(ERBB2):c.2331_2339dup (p.Gly778_Pro780dup)	Pathogenic	criteria provided, single submitter	3
376188	NM_004448.4(ERBB2):c.929C>A (p.Ser310Tyr)	Pathogenic	criteria provided, single submitter	1
13875	NM_004448.4(ERBB2):c.2313_2324dup (p.Tyr772_Ala775dup)	Likely pathogenic	criteria provided, single submitter	4
44985	NM_004448.4(ERBB2):c.2314_2325dup (p.Tyr772_Ala775dup)	Likely pathogenic	criteria provided, single submitter	2
44986	NM_004448.4(ERBB2):c.2320del (p.Met774fs)	Likely pathogenic	criteria provided, single submitter	1
44988	NM_004448.4(ERBB2):c.2326_2327insTGT (p.Gly776delinsValCys)	Likely pathogenic	criteria provided, single submitter	1
44989	NM_004448.4(ERBB2):c.2326_2327insTTT (p.Gly776delinsValCys)	Likely pathogenic	criteria provided, single submitter	1
44990	NM_004448.4(ERBB2):c.2326delinsTTAT (p.Gly776delinsLeuCys)	Likely pathogenic	criteria provided, single submitter	1
44993	NM_004448.4(ERBB2):c.2332_2340dup (p.Gly778_Pro780dup)	Likely pathogenic	criteria provided, single submitter	1
163409	NM_004448.4(ERBB2):c.2325_2326insTCCGTGATGGCT (p.Ala775_Gly776insSerValMetAla)	Likely pathogenic	criteria provided, single submitter	1
179590	NM_004448.4(ERBB2):c.2324_2325insCTCCGTGATGGC (p.Ala775_Gly776insSerValMetAla)	Likely pathogenic	criteria provided, single submitter	1
13876	NM_004448.4(ERBB2):c.2328_2336dup (p.Val777_Ser779dup)	Pathogenic	no assertion criteria provided	1
13878	NM_004448.4(ERBB2):c.2740G>A (p.Glu914Lys)	Pathogenic	no assertion criteria provided	1
13879	NM_004448.4(ERBB2):c.2326G>A (p.Gly776Ser)	Pathogenic	no assertion criteria provided	1
13880	NM_004448.4(ERBB2):c.2570A>G (p.Asn857Ser)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ERBB2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 2,300):

Position(s)	Effect	Δscore	Sites
17:39706988–39706989	acceptor_loss	1.0000	6
17:39707142–39707143	donor_loss	1.0000	5
17:39709453–39709454	donor_loss	1.0000	4
17:39709894	donor_gain	1.0000
17:39711854–39711855	acceptor_gain	1.0000	2
17:39715360–39715361	donor_loss	1.0000	5
17:39715444–39715445	acceptor_loss	1.0000	5
17:39715521	donor_gain	1.0000
17:39715537–39715538	donor_loss	1.0000	5
17:39723317–39723318	acceptor_loss	1.0000	6

AlphaMissense

3,129 missense substitutions predicted likely pathogenic (of 8,156 scored), across 673 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M833	9	0.989	0.999
M774	9	0.988	0.999
M979	9	0.976	0.999
M889	9	0.970	1.000
M953	9	0.963	0.996
M960	9	0.955	0.998
M955	9	0.951	1.000
M916	9	0.925	0.999
M801	9	0.899	0.994
N850	8	1.000	1.000
D863	8	1.000	1.000
H843	8	0.999	1.000
D845	8	0.999	1.000
D904	8	0.999	1.000
F731	8	0.997	1.000
S907	8	0.994	1.000
F969	8	0.994	1.000
F864	8	0.990	1.000
H901	8	0.976	0.997
F899	8	0.974	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.76e-08
Glioblastoma Multiforme (validation)	unfavorable	7.2e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000695
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	0.000698

Disease associations

OMIM: gene MIM:164870 | disease phenotypes: MIM:619465, MIM:137800, MIM:613659, MIM:109800, MIM:114500

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
Hirschsprung disease	Supportive	Autosomal dominant
lung cancer	Limited	Autosomal dominant
glioma susceptibility 1	Limited	Unknown
visceral neuropathy, familial, 2, autosomal recessive	Limited	Unknown

Mondo (10): visceral neuropathy, familial, 2, autosomal recessive (MONDO:0030399), lung adenocarcinoma (MONDO:0005061), non-small cell lung carcinoma (MONDO:0005233), glioma susceptibility 1 (MONDO:0024498), gastric cancer (MONDO:0001056), ovarian neoplasm (MONDO:0021068), urinary bladder cancer (MONDO:0001187), colorectal cancer (MONDO:0005575), lung cancer (MONDO:0008903), Hirschsprung disease (MONDO:0018309)

Orphanet (4): NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

49 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0001442	Typified by somatic mosaicism
HP:0001510	Growth delay
HP:0001513	Obesity
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001762	Talipes equinovarus
HP:0001824	Weight loss
HP:0001864	Clinodactyly of the 5th toe
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002251	Aganglionic megacolon
HP:0002716	Lymphadenopathy
HP:0002888	Ependymoma
HP:0003002	Breast carcinoma
HP:0003270	Abdominal distention
HP:0003477	Peripheral axonal neuropathy
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005214	Intestinal obstruction
HP:0006519	Alveolar cell carcinoma
HP:0006774	Ovarian papillary adenocarcinoma
HP:0008872	Feeding difficulties in infancy
HP:0009592	Astrocytoma
HP:0011284	Short-segment aganglionic megacolon
HP:0011459	Esophageal carcinoma
HP:0011968	Feeding difficulties
HP:0012126	Stomach cancer
HP:0012174	Glioblastoma multiforme
HP:0012450	Chronic constipation
HP:0012719	Functional abnormality of the gastrointestinal tract
HP:0012735	Cough
HP:0030078	Lung adenocarcinoma
HP:0030358	Non-small cell lung carcinoma
HP:0031369	Colon perforation
HP:0034754	Bilious emesis
HP:0100580	Barrett esophagus
HP:0100621	Dysgerminoma
HP:0100749	Chest pain
HP:0100806	Sepsis
HP:0410067	Increased level of L-fucose in urine
HP:6000224	Delayed passage of meconium

GWAS associations

17 associations:

Study	Trait	p-value
GCST008916_121	Asthma	2e-62
GCST005212_24	Asthma	2e-30
GCST008747_115	Estimated glomerular filtration rate	8e-29
GCST010002_175	Refractive error	1e-24
GCST007564_34	Asthma or allergic disease (pleiotropy)	4e-17
GCST008916_6	Asthma	2e-14
GCST005752_156	Systemic lupus erythematosus	2e-12
GCST007266_5	Adult asthma	4e-12
GCST008916_95	Asthma	3e-10
GCST003724_6	Bipolar disorder	5e-9
GCST008916_110	Asthma	5e-9
GCST003155_21	Systemic lupus erythematosus	8e-9
GCST012465_41	Bipolar disorder	2e-8
GCST000624_15	Ulcerative colitis	3e-8
GCST012465_30	Bipolar disorder	3e-8
GCST003144_8	Polycystic ovary syndrome	1e-6
GCST007235_3	Pancreatic ductal adenocarcinoma	1e-6

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL1824 (SINGLE PROTEIN), CHEMBL2111431 (PROTEIN FAMILY), CHEMBL2363049 (PROTEIN FAMILY), CHEMBL4106134 (PROTEIN COMPLEX), CHEMBL4630723 (PROTEIN COMPLEX), CHEMBL5465227 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ERBB2 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

38 curated-mechanism drugs:

Drug	Modality	Max phase
AFATINIB DIMALEATE	Small molecule	4
DACOMITINIB	Small molecule	4
LAPATINIB DITOSYLATE	Small molecule	4
MARGETUXIMAB	Antibody	4
MASOPROCOL	Small molecule	4
NERATINIB	Small molecule	4
PERTUZUMAB	Antibody	4
TRASTUZUMAB	Antibody	4
TRASTUZUMAB DERUXTECAN	Antibody drug conjugate	4
TRASTUZUMAB EMTANSINE	Antibody drug conjugate	4
TUCATINIB	Small molecule	4
ZANIDATAMAB	Antibody	4
CANERTINIB DIHYDROCHLORIDE	Small molecule	3
DISITAMAB VEDOTIN	Antibody drug conjugate	3
HEMAY-022	Unknown	3
KN-026	Unknown	3
PYROTINIB	Small molecule	3
TESEVATINIB	Small molecule	3
TRASTUZUMAB DUOCARMAZINE	Antibody drug conjugate	3
AEE-788	Small molecule	2
ALLITINIB	Small molecule	2
ANVATABART OPADOTIN	Antibody drug conjugate	2
BMS-690514	Small molecule	2
CP-724714	Small molecule	2
ERTUMAXOMAB	Antibody	2
GANCOTAMAB	Antibody	2
MDX-210	Unknown	2
MUBRITINIB	Small molecule	2
SAPITINIB	Small molecule	2
TRASTUZUMAB BOTIDOTIN	Antibody drug conjugate	2
VARLITINIB	Small molecule	2
AC-480	Small molecule	1
AV-412	Small molecule	1
CUDC-101	Small molecule	1
JNJ-26483327	Small molecule	1
S-222611	Unknown	1
TAK-285	Small molecule	1
TUXOBERTINIB	Small molecule	1

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes ERBB2 — the drug acts on the assembly or class, not necessarily on this subunit alone.

6 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
VANDETANIB	Epidermal growth factor receptor	4	4
ZENOCUTUZUMAB	ErbB-2/ErbB-3 heterodimer	2	4
POZIOTINIB	Epidermal growth factor receptor	4	3
MM-111	ErbB-2/ErbB-3 heterodimer	2	2
TARLOXOTINIB	Epidermal growth factor receptor	4	2
KBP5209	Epidermal growth factor receptor	4	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 568,581 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 83 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL2105712	AFATINIB DIMALEATE	4	3,441
CHEMBL2105719	DACOMITINIB	4	825
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,949
CHEMBL1201179	LAPATINIB DITOSYLATE	4	3,170
CHEMBL180022	NERATINIB	4	9,891
CHEMBL3989868	TUCATINIB	4	3,355
CHEMBL3707348	ACALABRUTINIB	4	4,772
CHEMBL633	AMIODARONE	4	30,023
CHEMBL296419	ASTEMIZOLE	4	21,684
CHEMBL290106	BITHIONOL	4	6,490
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL3545311	BRIGATINIB	4	5,988
CHEMBL2105717	CABOZANTINIB	4	11,799
CHEMBL71	CHLORPROMAZINE	4	46,206
CHEMBL104	CLOTRIMAZOLE	4	56,839
CHEMBL6067481	COLISTIN	4
CHEMBL5416410	DASATINIB	4	674
CHEMBL53463	DOXORUBICIN	4	317,622
CHEMBL305660	EBASTINE	4	10,106
CHEMBL808	ECONAZOLE	4
CHEMBL553	ERLOTINIB	4
CHEMBL1079742	ERLOTINIB HYDROCHLORIDE	4
CHEMBL726	FLUPHENAZINE	4
CHEMBL939	GEFITINIB	4
CHEMBL496	HEXACHLOROPHENE	4
CHEMBL1873475	IBRUTINIB	4
CHEMBL941	IMATINIB	4
CHEMBL554	LAPATINIB	4
CHEMBL4558324	LAZERTINIB	4
CHEMBL91	MICONAZOLE	4
CHEMBL58	MITOXANTRONE	4
CHEMBL4650319	MOBOCERTINIB	4
CHEMBL3353410	OSIMERTINIB	4
CHEMBL428647	PACLITAXEL	4
CHEMBL1171837	PONATINIB	4
CHEMBL1336	SORAFENIB	4
CHEMBL83	TAMOXIFEN	4
CHEMBL4071161	TIRABRUTINIB	4
CHEMBL24944	TRIBROMSALAN	4
CHEMBL24828	VANDETANIB	4
CHEMBL3936761	ZANUBRUTINIB	4
CHEMBL31965	CANERTINIB	3
CHEMBL545315	CANERTINIB DIHYDROCHLORIDE	3
CHEMBL3647420	PYROTINIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL1016	CANDESARTAN	3
CHEMBL491473	CEDIRANIB	3
CHEMBL954	ENCLOMIPHENE	3
CHEMBL1908391	MASITINIB	3
CHEMBL3545154	POZIOTINIB	3
CHEMBL4483575	REMIBRUTINIB	3
CHEMBL109480	TANESPIMYCIN	3
CHEMBL5314498	ZONGERTINIB	3
CHEMBL587723	AEE-788	2
CHEMBL1947204	ALLITINIB	2
CHEMBL483321	CP-724714	2
CHEMBL1614707	MUBRITINIB	2
CHEMBL2408045	SAPITINIB	2

Clinical evidence (CIViC)

Drug × variant × indication, from 214 curated evidence items; also 13 oncogenic, 11 functional, 3 prognostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

showing 30 of 191 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
ERBB2 Amplification	Trastuzumab	HER2 Positive Breast Cancer	Sensitivity/Response	CIViC A	EID1122 +2
ERBB2 Amplification	Trastuzumab	Gastric Adenocarcinoma	Sensitivity/Response	CIViC A	EID1499 +1
ERBB2 Amplification	Neratinib + Trastuzumab	HER2 Positive Breast Cancer	Sensitivity/Response	CIViC A	EID8047 +1
ERBB2 Amplification	Neratinib + Capecitabine	HER2 Positive Breast Cancer	Sensitivity/Response	CIViC A	EID8048 +1
ERBB2 Exon 20 Insertion	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11765 +1
ERBB2 A775_G776insTVMA	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11755
ERBB2 A775_G776insV	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11756
ERBB2 A775_G776insVVMA	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11757
ERBB2 A775_G776insYVMA	Zongertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12564
ERBB2 Amplification	Trastuzumab + Neratinib	HER2 Positive Breast Cancer	Sensitivity/Response	CIViC A	EID1113
ERBB2 Amplification	Capecitabine + Lapatinib	Breast Cancer	Sensitivity/Response	CIViC A	EID11247
ERBB2 Amplification	Letrozole + Lapatinib	Breast Cancer	Sensitivity/Response	CIViC A	EID11248
ERBB2 Amplification	Margetuximab	Breast Cancer	Sensitivity/Response	CIViC A	EID11249
ERBB2 Amplification	Trastuzumab + Tucatinib + Capecitabine	Breast Cancer	Sensitivity/Response	CIViC A	EID11250
ERBB2 Amplification	Pembrolizumab + Trastuzumab + Chemotherapy	Stomach Cancer	Sensitivity/Response	CIViC A	EID11251
ERBB2 Amplification	Trastuzumab + Pembrolizumab + Chemotherapy	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11252
ERBB2 Amplification	Trastuzumab	Stomach Cancer	Sensitivity/Response	CIViC A	EID11253
ERBB2 Amplification	Trastuzumab	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11254
ERBB2 Amplification	Trastuzumab + Chemotherapy	Gastroesophageal Junction Adenocarcinoma	Sensitivity/Response	CIViC A	EID11256
ERBB2 G776_V777delinsVCD	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11758
ERBB2 G776delinsLC	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11760
ERBB2 G776delinsVC	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11761
ERBB2 G778_P780dup	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11762
ERBB2 G778_S779insLPS	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11763
ERBB2 Kinase Domain Mutation OR ERBB2 Exon 20 Insertion	Sevabertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12808
ERBB2 L755A	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11752
ERBB2 L755M	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11753
ERBB2 L755P	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11754
ERBB2 L755P OR ERBB2 G776V OR ERBB2 G776delinsVC OR ERBB2 P780_Y781insGSP	Zongertinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12563
ERBB2 L755S	Trastuzumab Deruxtecan	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID12233

CIViC column: a representative evidence item (EID); +N = additional CIViC items supporting the same association.

Clinical-actionability assertions (CIViC AMP/ASCO/CAP)

Curated AMP/ASCO/CAP tier assertions — the clinical-actionability classification (Tier I highest) for this gene’s variants, distilling the CIViC evidence above into a tiered call.

4 CIViC assertions:

Molecular profile	Disease	Therapy	Type	AMP tier	Significance
ERBB2 Amplification	HER2 Positive Breast Cancer	Trastuzumab †	Predictive	Tier I - Level A	Sensitivity/Response
ERBB2 Amplification	HER2 Positive Breast Cancer	Neratinib †	Predictive	Tier I - Level A	Sensitivity/Response
ERBB2 G292R	Lung Non-small Cell Carcinoma		Oncogenic		Uncertain Significance
ERBB2 V777L	Lung Non-small Cell Carcinoma		Oncogenic		Likely Oncogenic

† an FDA-approved companion diagnostic exists for this assertion.

CIViC curated variants (47)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

L755P (missense variant), T798M (missense variant), T798I (missense variant), Activating Mutation (gene variant,gain of function variant), Exon 20 Insertion, Amplification (transcript amplification), D769H (missense variant), D769Y (missense variant), L755_T759del (inframe deletion), G309A (missense variant), L755S (missense variant), L755W (missense variant), Kinase Domain Mutation (protein altering variant), Y772_A775DUP (inframe insertion), SERUM LEVELS, R678Q (missense variant), R896C (missense variant), V777L (missense variant), G776V (missense variant), A775_G776insYVMA, G778_P780dup, G776delinsVC, V659E, S310F (missense variant), V842I (missense variant), G292R (missense variant), L755A, L755M (missense variant), A775_G776insTVMA, A775_G776insV, A775_G776insVVMA, G776_V777delinsVCD, G776delinsCV, G776delinsLC, G778_S779insLPS, L866M (missense variant), S310F/Y (missense variant), P780_Y781insGSP, Mutation (missense variant), Y772_A775dup (inframe insertion), G776L (missense variant), M774DELINSWLV (inframe indel), T862A (missense variant), V773A (missense variant), N857S (missense variant), H878Y (missense variant), Overexpression.

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1136201	Toxicity	3	trastuzumab	Breast Neoplasms;Drug Toxicity
rs1136201	Efficacy	3	carboplatin;docetaxel;trastuzumab	Breast Neoplasms

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1136201	ERBB2	3	2.50	2	trastuzumab;carboplatin;docetaxel;trastuzumab

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

3 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1136201	trastuzumab	Toxicity	Genotypes AG + GG is associated with increased risk of cardiotoxicity when treated with trastuzumab in women with Breast Neoplasms as compared to genotype AA.	PMID:26049584
rs1136201	carboplatin, docetaxel, trastuzumab	Efficacy	Allele G is associated with decreased response to carboplatin, docetaxel and trastuzumab in women with Breast Neoplasms.	PMID:30071039
rs1136201	trastuzumab	Toxicity	Allele G is associated with response to trastuzumab.	PMID:17693647

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type I RTKs: ErbB (epidermal growth factor) receptor family

Most potent curated ligand interactions (33 total), top 25:

Ligand	Action	Affinity	Parameter
MM-111	Binding	9.52	pKd
EGFR/ErbB-2/ErbB-4 inhibitor	Inhibition	8.96	pIC50
allitinib	Inhibition	8.52	pIC50
tuxobertinib	Inhibition	8.3	pIC50
poziotinib	Inhibition	8.28	pIC50
mubritinib	Inhibition	8.22	pIC50
AEE788	Inhibition	8.22	pIC50
pirotinib	Inhibition	8.19	pIC50
ibrutinib	Inhibition	8.19	pIC50
tucatinib	Inhibition	8.16	pIC50
compound 38 [PMID: 24915291]	Inhibition	8.15	pIC50
selatinib	Inhibition	8.07	pIC50
canertinib	Inhibition	8.05	pIC50
bizrolertinib	Inhibition	8.02	pIC50
pertuzumab	Inhibition	8.0	pIC50
mifanertinib	Inhibition	7.93	pIC50
CP-724714	Inhibition	7.92	pIC50
zongertinib	Inhibition	7.89	pIC50
lapatinib	Inhibition	7.89	pKi
afatinib	Inhibition	7.85	pIC50
sapitinib	Inhibition	7.85	pIC50
tesevatinib	Inhibition	7.8	pIC50
CUDC-101	Inhibition	7.8	pIC50
BMS-690514	Inhibition	7.72	pIC50
BMS-599626	Inhibition	7.49	pIC50

Binding affinities (BindingDB)

3941 measured of 4679 human assays (5100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
PD153035 Analog	IC50	0.006 nM
CHEMBL5288888	IC50	0.027 nM
CHEMBL3808884	EC50	0.04 nM
CHEMBL6132997	IC50	0.04 nM
CHEMBL5282641	IC50	0.053 nM
4-[4-[[(12aS)-8-methoxy-6-oxo-12a,13-dihydroindolo[2,1-c][1,4]benzodiazepin-9-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.06 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
2-Chloro-N-[4-(4,5-dichloro-2-fluoro-phenylamino)-quinazolin-6-yl]-acetamide	IC50	0.07 nM
CHEMBL4756368	IC50	0.07 nM
CHEMBL4787483	IC50	0.08 nM
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindazole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.09 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
CHEMBL4757145	IC50	0.09 nM
N-(2-((2,5-dichloropyrimidin-4- yl)amino)-6-methylphenyl)-N- ethylmethanesulfonamide	IC50	0.1 nM	US-20240343694: PYRIMIDINE DERIVATIVE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER COMPRISING SAME AS ACTIVE INGREDIENT
(E)-4-Dimethylamino-but-2-enoic acid [4-(4,5-dichloro-2-fluoro-phenylamino)-quinazolin-6-yl]-amide	IC50	0.11 nM
CHEMBL5614250	IC50	0.11 nM
CHEMBL3930620	IC50	0.12 nM
CHEMBL6146573	IC50	0.12 nM
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-(3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	IC50	0.13 nM	US-9187459: Quinazoline-7-ether compounds and methods of use
methyl 1-[4-[[4-[[4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methylimidazole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]indole-5-carboxylate	IC50	0.14 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
(3E)-2-amino-3-[hydroxy(phenyl)methylidene]-7,7-dimethyl-4-[4-(4-methylphenyl)sulfonylphenyl]-6,8-dihydro-4H-quinolin-5-one	IC50	0.14 nM	US-11505527: Tetrahydroquinoline derivatives and a process of preparation thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.15 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-methoxyindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.15 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(6-aminoindazole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.16 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(4-morpholin-4-yl-but-1-enyl)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide	IC50	0.16 nM
CHEMBL5574232	IC50	0.16 nM
CHEMBL5572504	IC50	0.16 nM
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-[5-(aminomethyl)indole-1-carbonyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.18 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methyl-N-[1-methyl-5-[[1-methyl-5-(5-methylsulfanylindole-1-carbonyl)pyrrol-3-yl]carbamoyl]pyrrol-3-yl]imidazole-2-carboxamide	IC50	0.2 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
CHEMBL4795165	IC50	0.2 nM
(2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide	IC50	0.22 nM
ethyl 4-[4-(benzenesulfonyl)phenyl]-7,7-dimethyl-5-oxo-2-(trifluoromethyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate	IC50	0.22 nM	US-11505527: Tetrahydroquinoline derivatives and a process of preparation thereof
CHEMBL3357639	IC50	0.26 nM
CHEMBL4098072	IC50	0.26 nM
CHEMBL3929484	IC50	0.27 nM
4-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(6-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1-methylimidazole-2-carboxamide	IC50	0.28 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
2-[4-[[(6aS)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6aH-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-N-[5-[[5-(5-aminoindole-1-carbonyl)-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-1,3-thiazole-4-carboxamide	IC50	0.3 nM	US-10143695: Pyrrolobenzodiazepines and conjugates thereof
N-[4-[(3-chloro-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-2-butynamide	IC50	0.3 nM
CHEMBL4078431	IC50	0.3 nM
CHEMBL4439338	IC50	0.3 nM
CHEMBL5186362	IC50	0.3 nM
CHEMBL3357642	IC50	0.31 nM
CHEMBL3818547	IC50	0.31 nM
CHEMBL4759112	IC50	0.32 nM
CHEMBL4793338	IC50	0.33 nM
CHEMBL4759697	IC50	0.34 nM
CHEMBL5178180	IC50	0.34 nM
CHEMBL3818062	IC50	0.35 nM
CHEMBL4759072	IC50	0.35 nM
CHEMBL4744985	IC50	0.35 nM
CHEMBL4794998	IC50	0.36 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM

ChEMBL bioactivities

3453 potent at pChembl≥5 of 3763 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	IC50	0.04	nM	CHEMBL6132997
10.22	IC50	0.06	nM	IMATINIB
10.22	IC50	0.06	nM	CHEMBL5939267
10.05	IC50	0.09	nM	CHEMBL6019933
9.85	IC50	0.14	nM	CHEMBL5221067
9.85	IC50	0.14	nM	CHEMBL5966664
9.82	IC50	0.15	nM	CHEMBL5902815
9.82	IC50	0.15	nM	CHEMBL5980010
9.80	IC50	0.16	nM	CHEMBL5178703
9.80	IC50	0.16	nM	CHEMBL6019427
9.74	IC50	0.18	nM	CHEMBL6036674
9.70	IC50	0.2	nM	CHEMBL5956952
9.55	IC50	0.28	nM	CHEMBL5929658
9.54	IC50	0.29	nM	CHEMBL5939267
9.52	IC50	0.3	nM	CHEMBL5980010
9.52	IC50	0.3	nM	CHEMBL5955178
9.51	IC50	0.31	nM	CHEMBL6019933
9.47	IC50	0.34	nM	CHEMBL5977738
9.46	IC50	0.35	nM	CHEMBL5956952
9.40	IC50	0.4	nM	CHEMBL5853980
9.38	IC50	0.42	nM	CHEMBL5178703
9.37	IC50	0.43	nM	CHEMBL5178703
9.37	IC50	0.43	nM	CHEMBL5902815
9.30	IC50	0.5	nM	CHEMBL3344216
9.30	IC50	0.5	nM	CHEMBL437890
9.30	IC50	0.5	nM	CHEMBL204638
9.26	IC50	0.55	nM	CHEMBL5966664
9.25	IC50	0.56	nM	CHEMBL5178703
9.25	IC50	0.56	nM	SORAFENIB
9.24	IC50	0.58	nM	CHEMBL5978603
9.23	IC50	0.59	nM	CHEMBL5956952
9.22	IC50	0.6	nM	CHEMBL5980010
9.22	IC50	0.6	nM	CHEMBL6019427
9.22	IC50	0.6	nM	CHEMBL5881155
9.20	IC50	0.63	nM	CHEMBL5939267
9.18	IC50	0.66	nM	CHEMBL6019933
9.18	IC50	0.66	nM	CHEMBL5850421
9.17	IC50	0.67	nM	CHEMBL5876925
9.16	IC50	0.69	nM	CHEMBL2387001
9.15	IC50	0.7	nM	CHEMBL203599
9.15	IC50	0.7	nM	CHEMBL204638
9.15	IC50	0.7	nM	CHEMBL5955178
9.14	IC50	0.73	nM	CHEMBL5929658
9.12	Kd	0.75	nM	IBRUTINIB
9.10	IC50	0.8	nM	CHEMBL203661
9.10	IC50	0.8	nM	CHEMBL203599
9.09	IC50	0.81	nM	CHEMBL6036674
9.08	IC50	0.84	nM	CHEMBL5902815
9.08	IC50	0.83	nM	CHEMBL5966664
9.05	IC50	0.89	nM	CHEMBL2387000

PubChem BioAssay actives

2566 with measured affinity, of 5593 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(2,6-dioxopiperidin-3-yl)-5-[7-[4-[3-[6-methoxy-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]heptylamino]isoindole-1,3-dione	2213510: Inhibition of HER2 (unknown origin)	ic50	<0.0001	uM
N-(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)-2-(1H-pyrazolo[5,4-b]pyridin-3-ylamino)acetamide	1916785: Inhibition of HER2 (unknown origin) incubated for 1 hr in presence of ATP by Kinase-Glo Plus luminescence kinase assay	ic50	0.0001	uM
Imatinib	1916785: Inhibition of HER2 (unknown origin) incubated for 1 hr in presence of ATP by Kinase-Glo Plus luminescence kinase assay	ic50	0.0001	uM
(Z)-N-[7-ethoxy-4-[3-methyl-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]-2-fluoro-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905774: Inhibition of HER2 V777L mutant (unknown origin) incubated for 120 mins in presence of 33P-ATP by P81 ion exchange cellulose chromatography	ic50	0.0002	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0005	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260899: Inhibition of HER stimulated human erbB autophosphorylation in MDA-MB-453 cells	ic50	0.0005	uM
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(1S)-1-(dimethylamino)-2-methylsulfonylethyl]furan-2-yl]quinazolin-4-amine	1168534: Inhibition of HER2 (unknown origin) assessed as reduction in autophosphorylation by ELISA method	ic50	0.0005	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0007	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-methoxy-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0007	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0008	uM
Ibrutinib	1878102: Binding affinity to ERBB2 (unknown origin) assessed as dissociation constant by KINOMEscan analysis	kd	0.0008	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0009	uM
(2S)-N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]pyrrolidine-2-carboxamide;hydrochloride	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0009	uM
(2R)-2-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]quinazolin-5-yl]oxy-N,N-dimethylpropanamide	315250: Inhibition of ebrB2	ic50	0.0010	uM
1-[4-[2-[[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperazin-1-yl]ethanone	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-(2-morpholin-4-ylethoxy)-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[4-[(3-fluorophenyl)methoxy]-3-methylanilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-(3-morpholin-4-ylpropoxy)-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
1-[2-[[4-[3-chloro-4-[(6-methyl-3-pyridinyl)oxy]anilino]-1H-pyrazolo[5,4-d]pyrimidin-3-yl]oxy]ethyl]piperidin-4-ol	320572: Inhibition of erbB2	ic50	0.0010	uM
(2R)-N,N-dimethyl-2-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]quinazolin-5-yl]oxypropanamide	315250: Inhibition of ebrB2	ic50	0.0010	uM
N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-[(2R)-1-(dimethylamino)propan-2-yl]oxyquinazolin-4-amine	404519: Inhibition of HER2	ic50	0.0010	uM
(Z)-N-[7-ethoxy-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]-2-fluoro-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	2213515: Inhibition of HER2 D769H mutant (unknown origin)	ic50	0.0010	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-isoquinolin-6-yl-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450721: Inhibition of recombinant ErbB2 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0010	uM
1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0010	uM
N-(1-benzylindazol-5-yl)-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine	404519: Inhibition of HER2	ic50	0.0010	uM
2-amino-N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-2-methylpropanamide	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0010	uM
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3-[2-(oxazepan-2-yl)ethoxy]-1H-pyrazolo[5,4-d]pyrimidin-4-amine	320572: Inhibition of erbB2	ic50	0.0010	uM
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[1-(methylamino)-2-methylsulfonylethyl]furan-2-yl]quinazolin-4-amine	1168534: Inhibition of HER2 (unknown origin) assessed as reduction in autophosphorylation by ELISA method	ic50	0.0010	uM
Neratinib	410944: Inhibition of ERBb2 by HTRF assay	ic50	0.0010	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]prop-2-enamide	68096: Inhibition of heregulin-stimulated autophosphorylation of ERBB2 receptor kinase in MDA-MB-453 cells.	ic50	0.0011	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-ynamide	260896: Inhibition of erbB2 fusion protein expressed in baculovirus by ELISA	ic50	0.0011	uM
(E)-N-[7-hydroxy-4-(4-imidazo[1,2-c]pyrimidin-7-yloxy-3-methylanilino)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0011	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2,4-dichlorophenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0012	uM
1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0013	uM
6-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-2,3-dihydroisoindol-1-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0013	uM
(E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[4-[3-methyl-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0014	uM
(E)-N-[7-hydroxy-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide	1905726: Inhibition of wild type human GST-tagged HER2 (676 to end residues) expressed in baculovirus infected Sf9 cells incubated for 30 mins in presence of ATP by HTRF analysis	ic50	0.0014	uM
1-[4-[4-(3-chloro-2-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one	1951290: Inhibition of HER2 (unknown origin)	ic50	0.0014	uM
(E)-3-[(2R)-1-methylpyrrolidin-2-yl]-N-[4-[3-methyl-4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)anilino]quinazolin-6-yl]prop-2-enamide	2213510: Inhibition of HER2 (unknown origin)	ic50	0.0014	uM
(Z)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-ethoxyquinazolin-6-yl]-4-(dimethylamino)-2-fluorobut-2-enamide	1171421: Inhibition of wild type HER2 (unknown origin) incubated for 5 mins by HTRF assay	ic50	0.0014	uM
(E)-N-[6-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-2,4,6-triazatricyclo[7.3.1.05,13]trideca-1(13),2,4,9,11-pentaen-10-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0015	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-5-(3-methoxyphenyl)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0015	uM
7-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-1,3-dihydroindol-2-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0015	uM
(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-5-(3-methylphenyl)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	2103212: Inhibition of wild type HER2 (unknown origin) using 4 x ULightTM-labeled Ploy GT peptide substrate measured after 180 mins	ic50	0.0016	uM
4-[2-chloro-4-[[5-(2-hydroxyethyl)pyrrolo[3,2-d]pyrimidin-4-yl]amino]phenoxy]-1,3-dihydroindol-2-one	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0016	uM
N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]acetamide	670126: Inhibition of N-terminus peptide-tagged human recombinant HER2 expressed using baculovirus infection system using [gamma-33P]-ATP preincubated with compound for 5 mins measured after 10 mins by scintillation counting	ic50	0.0016	uM

CTD chemical–gene interactions

212 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Fluorouracil	decreases reaction, decreases response to substance, decreases activity, decreases phosphorylation, increases reaction (+5 more)	12
Doxorubicin	affects response to substance, increases phosphorylation, increases reaction, affects reaction, decreases reaction (+5 more)	11
sodium arsenite	affects reaction, increases abundance, increases reaction, affects expression, affects phosphorylation (+7 more)	8
Lapatinib	decreases expression, decreases response to substance, increases phosphorylation, decreases phosphorylation, increases reaction (+2 more)	8
Estradiol	increases expression, increases reaction, decreases reaction, affects cotreatment, decreases expression	7
Tamoxifen	increases activity, increases phosphorylation, decreases reaction, increases response to substance, decreases response to substance	7
Cisplatin	decreases reaction, decreases response to substance, affects cotreatment, decreases expression, increases expression (+1 more)	6
Curcumin	decreases reaction, decreases response to substance, increases degradation, decreases activity, decreases phosphorylation (+3 more)	6
Cyclophosphamide	decreases response to substance, affects cotreatment, affects response to substance	6
geldanamycin	increases reaction, decreases expression, increases ubiquitination, increases degradation, affects binding (+1 more)	5
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, increases degradation	5
Resveratrol	decreases phosphorylation, decreases reaction, increases expression, increases reaction, affects cotreatment (+1 more)	5
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	5
Quercetin	decreases reaction, increases ubiquitination, increases reaction, decreases phosphorylation, increases expression (+5 more)	5
Tetrachlorodibenzodioxin	affects expression, decreases expression, increases expression	5
bisphenol F	affects cotreatment, decreases methylation, increases expression	4
beta-hexachlorocyclohexane	increases reaction, decreases reaction, increases activity, increases expression, affects binding	4
Fulvestrant	affects response to substance, decreases expression, decreases reaction, increases expression, affects cotreatment (+1 more)	4
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, increases expression (+1 more)	4
Cycloheximide	increases degradation, increases reaction, affects cotreatment, decreases expression	4
Etoposide	increases expression, decreases expression, decreases reaction, decreases response to substance, affects response to substance	4
Valproic Acid	affects expression, decreases expression	4
Paclitaxel	affects response to substance, increases expression, decreases reaction, decreases response to substance, decreases activity (+2 more)	4
arsenite	increases expression, increases phosphorylation, affects reaction, increases secretion, affects response to substance (+3 more)	3
afimoxifene	affects binding, decreases reaction, increases reaction, decreases expression, decreases response to substance	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, decreases response to substance, increases expression, affects binding, increases reaction (+1 more)	3
tanespimycin	decreases expression, increases degradation	3
Docetaxel	affects cotreatment, affects response to substance, increases response to substance	3
Vorinostat	decreases expression, increases degradation, increases ubiquitination	3
Arsenic	increases abundance, increases reaction, affects cotreatment, increases expression, affects expression (+5 more)	3

ChEMBL screening assays

1221 unique, capped per target: 1136 binding, 79 functional, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001230	Binding	Inhibition of ERBB2	The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors. — *Bioorg Med Chem Lett*
CHEMBL1963780	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ERBB2	PubChem BioAssay data set
CHEMBL4023690	ADMET	Inhibition of recombinant human cytoplasmic His-tagged ERBB2 expressed in baculovirus at 1 uM by Z’-LYTE assay	Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development. — *J Med Chem*

Cellosaurus cell lines

95 cell lines: 48 cancer cell line, 27 spontaneously immortalized cell line, 13 transformed cell line, 5 factor-dependent cell line, 2 conditionally immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0124	435.eB	Cancer cell line	Male
CVCL_0U80	MCF-7/HER2-18	Cancer cell line	Female
CVCL_1188	ECC10	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_1452	NCI-ADR-RES	Cancer cell line	Female
CVCL_1629	OVCAR-8	Cancer cell line	Female
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_1859	CCRF-HSB-2	Cancer cell line	Male
CVCL_1Y12	HSB2/GS	Cancer cell line	Male
CVCL_3033	MTSV1-7 ce1	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 597 trials:

NCT	Phase	Status	Title
NCT00158041	Phase 4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	Phase 4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	Phase 4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	Phase 4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	Phase 4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	Phase 4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	Phase 4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	Phase 4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	Phase 4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	Phase 4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	Phase 4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	Phase 4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	Phase 4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	Phase 4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	Phase 4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	Phase 4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	Phase 4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	Phase 4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	Phase 4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	Phase 4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	Phase 4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	Phase 4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	Phase 4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	Phase 4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	Phase 4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	Phase 4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	Phase 4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	Phase 4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	Phase 4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	Phase 4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	Phase 4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	Phase 4	UNKNOWN	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	Phase 4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	Phase 4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	Phase 4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	Phase 4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT07743333	Phase 4	COMPLETED	Nebulized Lidocaine And Ketamine Before Fiberoptic Bronchoscopy
NCT07761351	Phase 4	RECRUITING	A Randomized Controlled Trial Comparing Percutaneous CT-Guided Biopsy and Shape-Sensing Robotic-Assisted Bronchoscopy
NCT07802847	Phase 4	NOT_YET_RECRUITING	Innovative and Cooperative Pathway Integrating Oncogeriatric, Pharmaceutical and Pharmacological Follow-up in Elderly Patients.
NCT00190697	Phase 4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00719017	Phase 4	UNKNOWN	Upper Vaginectomy Versus Brachytherapy in Patients With Early Stage Endometrial Cancer Treated With Laparoscopic Surgery
NCT02543710	Phase 4	RECRUITING	Biomarker Guided Treatment in Gynaecological Cancer
NCT03349463	Phase 4	UNKNOWN	Evaluation of Fluciclovine Uptake in Patients With Cervical, Ovarian Epithelial or Endometrial Cancers.
NCT03752606	Phase 4	COMPLETED	Application of Tachosil During Lymphadenectomy
NCT05949424	Phase 4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT06049693	Phase 4	COMPLETED	Iron Prehabilitation in Endometrial Cancer
NCT06726291	Phase 4	RECRUITING	Akynzeo as Antiemetic Treatment in Patients With Endometrial Cancer
NCT06871787	Phase 4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT07281547	Phase 4	NOT_YET_RECRUITING	Low Dose Aspirin to Lower Inflammation and Prevent Endometrial Cancer in Postmenopausal Women With Non-atrophic Endometrial Changes and Pain
NCT07462663	Phase 4	NOT_YET_RECRUITING	SHAPE-ENDO: Pilot Randomized Trial of Multimodal Pre-Surgical Optimization Versus Standard Surgery in Patients With Obesity and Early-Stage Endometrial Cancer
NCT00002550	Phase 3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	Phase 3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00002623	Phase 3	COMPLETED	Chemotherapy Followed by Surgery or Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer
NCT00002822	Phase 3	COMPLETED	Combination Chemotherapy Followed by Radiation Therapy in Patients With Small Cell Lung Cancer
NCT00002823	Phase 3	COMPLETED	Combination Chemotherapy Compared With No Treatment Following Surgery in Treating Patients With Non-small Cell Lung Cancer
NCT00002858	Phase 3	UNKNOWN	Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Small Cell Lung Cancer
NCT00002911	Phase 3	COMPLETED	Marimastat in Treating Patients With Stage III Non-small Cell Lung Cancer
NCT00003011	Phase 3	COMPLETED	Marimastat Following Chemotherapy in Treating Patients With Small Cell Lung Cancer
NCT00003053	Phase 3	UNKNOWN	Combination Chemotherapy in Treating Patients With Stage I, II, or IIIA Non-small Cell Lung Cancer That Has Been Surgically Removed

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ERBB2 across ~30M SureChEMBL compounds — explore on Sugi Predict.