AMPH

Summary

AMPH (amphiphysin, HGNC:471) is a protein-coding gene on chromosome 7p14.1, encoding Amphiphysin (P49418). May participate in mechanisms of regulated exocytosis in synapses and certain endocrine cell types.

This gene encodes a protein associated with the cytoplasmic surface of synaptic vesicles. A subset of patients with stiff-man syndrome who were also affected by breast cancer are positive for autoantibodies against this protein. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences have not been determined. A pseudogene of this gene is found on chromosome 11.

Source: NCBI Gene 273 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 119 total — 3 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 29 tissues, sQTL in 9 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.70 (unconstrained)
• MANE Select transcript: NM_001635
• Interaction hub: 2,026 STRING partners (top 7% of genes corpus-wide)
• Notable: 119 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:471
Approved symbol	AMPH
Name	amphiphysin
Location	7p14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000078053
Ensembl biotype	protein_coding
OMIM	600418
Entrez	273

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000356264

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

ENST00000356264, ENST00000325590, ENST00000441628, ENST00000450124, ENST00000460887, ENST00000462072, ENST00000467580, ENST00000471913, ENST00000475581, ENST00000873035, ENST00000873036, ENST00000873037, ENST00000962297, ENST00000962298, ENST00000962299, ENST00000962300, ENST00001138491

RefSeq mRNA: 2 — MANE Select: NM_001635 NM_001635, NM_139316

CCDS: CCDS47574, CCDS5456

Canonical transcript exons

ENST00000356264 — 21 exons

Exon	Start	End
ENSE00001023141	38432189	38432212
ENSE00001363931	38429842	38429865
ENSE00001602804	38383704	38384925
ENSE00001605286	38461283	38461411
ENSE00001607557	38476862	38476969
ENSE00001611965	38503650	38503704
ENSE00001646088	38534931	38535011
ENSE00001723487	38465467	38465549
ENSE00001727100	38466173	38466248
ENSE00001730994	38389804	38389905
ENSE00001770901	38491050	38491145
ENSE00001772878	38462975	38463113
ENSE00001784795	38436272	38436388
ENSE00001792437	38494433	38494527
ENSE00001792678	38475331	38475416
ENSE00001865805	38631283	38631373
ENSE00003471561	38426954	38426986
ENSE00003473921	38422421	38422477
ENSE00003562385	38394005	38394214
ENSE00003595838	38417825	38417950
ENSE00003657767	38391748	38392017

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 98.09.

FANTOM5 (CAGE): breadth broad, TPM avg 7.0973 / max 444.9620, expressed in 868 samples.

Highest expression (Bgee): middle temporal gyrus, endothelial cell, frontal pole, paraflocculus, pons.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AMPH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 9 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	eqtl	3.8e-95	+1.31	7:38475741:C:G
Skin Sun Exposed Lower leg	eqtl	7.9e-89	+1.15	7:38475729:G:C
Nerve Tibial	eqtl	8.1e-77	+1.22	7:38488577:C:T
Muscle Skeletal	eqtl	2.9e-71	+0.95	7:38472217:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.8e-64	+0.90	7:38472217:C:T
Adipose Visceral Omentum	eqtl	1.3e-51	+1.01	7:38470929:A:T
Thyroid	eqtl	4.1e-39	+0.78	7:38492535:G:C
Artery Tibial	eqtl	4.6e-18	+0.61	7:38460448:A:G
Esophagus Gastroesophageal Junction	eqtl	5.9e-18	+0.80	7:38447739:AACAG:A
Breast Mammary Tissue	eqtl	1.0e-17	+0.51	7:38466503:T:C
Heart Atrial Appendage	eqtl	4.7e-17	+0.72	7:38453473:C:G
Cells EBV-transformed lymphocytes	eqtl	5.1e-11	-0.64	7:38358879:C:CAA
Colon Sigmoid	eqtl	1.4e-10	+0.47	7:38472702:G:A
Esophagus Muscularis	eqtl	4.2e-10	+0.59	7:38475729:G:C
Cells Cultured fibroblasts	eqtl	2.3e-09	+0.20	7:38682090:G:A
Skin Sun Exposed Lower leg	sqtl	1.6e-08	-0.70	7:38492135:A:G
Stomach	eqtl	4.6e-08	+0.36	7:38459902:GAC:G
Colon Transverse	eqtl	9.8e-08	+0.31	7:38455094:C:T
Testis	eqtl	1.3e-06	+0.36	7:38398990:A:T
Artery Coronary	eqtl	2.8e-06	+0.60	7:38455094:C:T

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
83708	6.2831	826
83711	0.3854	197
83709	0.2639	105
83710	0.1648	80

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	98.09	gold quality
endothelial cell	CL:0000115	96.85	gold quality
frontal pole	UBERON:0002795	96.51	gold quality
paraflocculus	UBERON:0005351	96.24	gold quality
pons	UBERON:0000988	95.24	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.20	gold quality
cerebellar vermis	UBERON:0004720	94.88	gold quality
prefrontal cortex	UBERON:0000451	94.72	gold quality
cerebellar cortex	UBERON:0002129	94.52	gold quality
cerebellar hemisphere	UBERON:0002245	94.47	gold quality
orbitofrontal cortex	UBERON:0004167	94.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.44	gold quality
cerebellum	UBERON:0002037	94.37	gold quality
frontal cortex	UBERON:0001870	94.18	gold quality
superior frontal gyrus	UBERON:0002661	94.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.83	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.57	gold quality
neocortex	UBERON:0001950	93.46	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.40	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.23	gold quality
right frontal lobe	UBERON:0002810	93.06	gold quality
postcentral gyrus	UBERON:0002581	92.67	gold quality
cerebral cortex	UBERON:0000956	92.28	gold quality
cingulate cortex	UBERON:0003027	92.09	gold quality
parietal lobe	UBERON:0001872	92.08	gold quality
anterior cingulate cortex	UBERON:0009835	92.03	gold quality
primary visual cortex	UBERON:0002436	91.24	gold quality
entorhinal cortex	UBERON:0002728	90.63	gold quality
occipital lobe	UBERON:0002021	90.22	gold quality
cortical plate	UBERON:0005343	90.19	gold quality
substantia nigra pars compacta	UBERON:0001965	88.77	gold quality
temporal lobe	UBERON:0001871	88.69	gold quality
brain	UBERON:0000955	88.67	gold quality
telencephalon	UBERON:0001893	88.41	gold quality
central nervous system	UBERON:0001017	88.35	gold quality
hypothalamus	UBERON:0001898	88.28	gold quality
forebrain	UBERON:0001890	88.22	gold quality
Ammon’s horn	UBERON:0001954	87.69	gold quality
pituitary gland	UBERON:0000007	87.31	gold quality
amygdala	UBERON:0001876	86.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.28	gold quality
ventricular zone	UBERON:0003053	86.20	gold quality
substantia nigra pars reticulata	UBERON:0001966	85.93	gold quality
superior vestibular nucleus	UBERON:0007227	85.78	gold quality
adenohypophysis	UBERON:0002196	85.08	gold quality
ganglionic eminence	UBERON:0004023	84.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.08	gold quality
substantia nigra	UBERON:0002038	83.37	gold quality
midbrain	UBERON:0001891	83.35	gold quality
CA1 field of hippocampus	UBERON:0003881	83.14	gold quality
dorsal root ganglion	UBERON:0000044	82.68	gold quality
nucleus accumbens	UBERON:0001882	81.35	gold quality
mucosa of stomach	UBERON:0001199	80.29	gold quality
islet of Langerhans	UBERON:0000006	80.28	gold quality
caudate nucleus	UBERON:0001873	79.86	gold quality
ventral tegmental area	UBERON:0002691	79.11	gold quality
adult organism	UBERON:0007023	78.99	gold quality
putamen	UBERON:0001874	78.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.70	gold quality
dorsal plus ventral thalamus	UBERON:0001897	78.57	gold quality
medulla oblongata	UBERON:0001896	78.37	gold quality
spinal cord	UBERON:0002240	78.32	gold quality
middle frontal gyrus	UBERON:0002702	78.03	silver quality
omental fat pad	UBERON:0010414	76.87	gold quality
descending thoracic aorta	UBERON:0002345	76.82	gold quality
peritoneum	UBERON:0002358	76.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	76.79	gold quality
cartilage tissue	UBERON:0002418	76.76	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.72	gold quality
trigeminal ganglion	UBERON:0001675	76.61	gold quality
secondary oocyte	CL:0000655	76.55	gold quality
popliteal artery	UBERON:0002250	76.30	gold quality
tibial artery	UBERON:0007610	76.29	gold quality
endocervix	UBERON:0000458	75.93	gold quality
aorta	UBERON:0000947	75.70	gold quality
left uterine tube	UBERON:0001303	75.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.29	gold quality
lower esophagus	UBERON:0013473	75.23	gold quality
thoracic aorta	UBERON:0001515	75.08	gold quality
body of uterus	UBERON:0009853	74.94	gold quality
gastrocnemius	UBERON:0001388	74.90	gold quality
ascending aorta	UBERON:0001496	74.80	gold quality
muscle of leg	UBERON:0001383	74.45	gold quality
sperm	CL:0000019	74.37	gold quality
adipose tissue	UBERON:0001013	74.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	74.13	gold quality
calcaneal tendon	UBERON:0003701	73.62	gold quality
connective tissue	UBERON:0002384	73.36	gold quality
apex of heart	UBERON:0002098	73.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.06	gold quality
ectocervix	UBERON:0012249	72.94	gold quality
embryo	UBERON:0000922	72.69	gold quality
gall bladder	UBERON:0002110	72.44	gold quality
male germ cell	CL:0000015	72.41	silver quality
muscle layer of sigmoid colon	UBERON:0035805	72.38	gold quality
smooth muscle tissue	UBERON:0001135	71.83	gold quality
stromal cell of endometrium	CL:0002255	71.72	gold quality
tibialis anterior	UBERON:0001385	71.38	silver quality
right uterine tube	UBERON:0001302	71.06	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.30
E-GEOD-84465	yes	7.11
E-MTAB-7303	no	612.27

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 75 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	164.2
Cerebellum	tissue	143.4	high
Frontal cortex	tissue	129.5
Thalamus	tissue	110.1
Cerebral cortex	tissue	107.9	high
Somatosensory cortex	tissue	107.9
Prefrontal cortex	tissue	103.7
Temporal cortex	tissue	100.7
Occipital cortex	tissue	100.7
Hippocampal formation	tissue	100.4
Pons	tissue	99.1
Motor cortex	tissue	98.7
Amygdala	tissue	98.1
Olfactory bulb	tissue	98.1
Retrosplenial and cingulate cortex	tissue	97.9
Entorhinal cortex	tissue	92.7
Retrosplenial cortex	tissue	89.4
Superior colliculi	tissue	87.1
Midbrain	tissue	83.7
Insular cortex	tissue	82.7
Substantia nigra	tissue	74.6
Hippocampus	tissue	71.9	medium
Caudate putamen	tissue	71.6
Medulla oblongata	tissue	69.3
Hypothalamus	tissue	68.1
Retina	tissue	61.1
Spinal cord	tissue	52.4
Periaqueductal gray	tissue	52.2
Septum	tissue	50.9
Ventral forebrain	tissue	45.9
Putamen	tissue	43.2
Basal ganglia	tissue	42.6	medium
Locus coeruleus	tissue	37.0
Nucleus accumbens	tissue	22.0
Pituitary gland	tissue	20.1
Corpus callosum	tissue	13.5
Tongue	tissue	9.0
Cervix	tissue	5.5	not detected
Heart muscle	tissue	5.0	not detected
Choroid plexus	tissue	4.5
Fallopian tube	tissue	4.1	not detected
Smooth muscle	tissue	3.5	not detected
Endometrium 1	tissue	3.5	not detected
Epididymis	tissue	3.2	not detected
Vagina	tissue	3.0	not detected
Esophagus	tissue	3.0	not detected
Gallbladder	tissue	2.8	not detected
Seminal vesicle	tissue	2.7	not detected
Adipose tissue	tissue	2.6	not detected
Testis	tissue	2.3	not detected
Kidney	tissue	2.3	low
Skeletal muscle	tissue	2.0	not detected
Ovary	tissue	1.8	not detected
Pancreas	tissue	1.7	low
Breast	tissue	1.4	not detected
Urinary bladder	tissue	1.4	not detected
Appendix	tissue	1.4	not detected
Rectum	tissue	1.3	low
Prostate	tissue	1.2	not detected
Adrenal gland	tissue	1.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Precentral gyrus (120.0), Arcuate nucleus (119.5), Paracentral lobule, anterior (117.1), Posterior insular cortex (117.1), Superior temporal gyrus (117.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

showing 30 of 97 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220

Functional genomics

gnomAD constraint: pLI 1.61e-06, LOEUF 0.697, missense Z 1.14 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000356264 splits into 2 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
7:38,384,821–38,465,509	554 / 575.6	0.96	no
7:38,465,510–38,631,351	205 / 287.9	0.71	no

Literature-anchored findings (GeneRIF, showing 16)

• Female patient with amphiphysin autoantibodies and siff leg syndrome due to small cell cancer of the lung. (PMID:16671079)
• Amphiphysin I (Amph I) is a minibrain kinase/dual-specificity tyrosine phosphorylation-regulated kinase substrate. Amph I phosphorylation changes the recruitment of endophilin at the endocytic sites. (PMID:16733250)
• This study demonstrates that the analysis of the molecular interaction energy components between peptides and the SH3 domain can successfully characterize the binding interface. (PMID:18206907)
• Analyses of Gaussian distribution models showed that diversified properties contribute to the interactions between the SH3 domain and of amphiphysin and peptides. (PMID:18814309)
• structure-based approach to prediction of peptide-binding behavior of SH3 domain of amphiphysin-1: statistical modeling (PMID:19669081)
• investigation of binding affinities of decapeptide ligands with amphiphysin SH3 domain using QSAR models (PMID:20214647)
• We propose that antibody-mediated amphiphysin deficiency may account for anxiety behavior in stiff person syndrome (PMID:22331304)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• AMPH1 protein level is reduced in transgenic mouse brain proteins. in the brainstem of nontransgenic and terminally ill JNPL3 transgenic mice. (PMID:22975846)
• It is a nerve protein and its autoantibody causes paraneoplastic neurological syndromes. (PMID:25087559)
• We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies. (PMID:26506308)
• The data show that the dynamin-amphiphysin helices are rearranged to form clusters upon GTP hydrolysis and membrane constriction occurs at protein-uncoated regions flanking the clusters. (PMID:29357276)
• the anti-oncogenic function of AMPH-1 in lung cancer in vitro and in vivo, is reported. (PMID:30143925)
• AMPH1 functions as a tumour suppressor in ovarian cancer via the inactivation of PI3K/AKT pathway. (PMID:32476271)
• Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction. (PMID:34018922)
• Amphiphysin-IgG autoimmune sciatic neuropathy and facial neuropathy related to primary central nervous system lymphoma: A case report. (PMID:37556888)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	amph	ENSDARG00000007663
mus_musculus	Amph	ENSMUSG00000021314
rattus_norvegicus	Amph	ENSRNOG00000059510
drosophila_melanogaster	Amph	FBGN0027356
caenorhabditis_elegans		WBGENE00010272

Paralogs (3): BIN2 (ENSG00000110934), BIN1 (ENSG00000136717), BIN3 (ENSG00000147439)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103574) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cued conditioning behavior	1
abnormal spatial learning	1
abnormal contextual conditioning behavior	1
abnormal spermiogenesis	1
premature death	1
abnormal Sertoli cell morphology	1
tonic seizures	1
increased susceptibility to pharmacologically induced seizures	1
abnormal synaptic vesicle recycling	1
decreased spermatid number	1
impaired spermiation	1

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	Q5ZKL7	78.9%	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
TRG	protein-coding	6965
TRG-AS1	ncRNA	100506776
POU6F2-AS2	ncRNA	100689074
POU6F2	protein-coding	11281
VPS41	protein-coding	27072
TARP	protein-coding	445347
STARD3NL	protein-coding	83930

Protein

Protein identifiers

Amphiphysin — P49418 (reviewed: P49418)

All UniProt accessions (3): H0Y5S4, H0Y7T8, P49418

UniProt curated annotations — full annotation on UniProt →

Function. May participate in mechanisms of regulated exocytosis in synapses and certain endocrine cell types. May control the properties of the membrane associated cytoskeleton.

Subunit / interactions. Heterodimer with BIN1. Binds SH3GLB1. Interacts with REPS1 and SGIP1. Binds AP2A2. Interacts with AP2B1. Interacts with DNM1 and SYNJ1.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Cytoplasm. Cytoskeleton.

Tissue specificity. Neurons, certain endocrine cell types and spermatocytes.

Miscellaneous. Antibodies against AMPH are detected in patients with stiff-man syndrome, a rare disease of the central nervous system characterized by progressive rigidity of the body musculature with superimposed painful spasms.

Isoforms (2)

UniProt ID	Names	Canonical?
P49418-1	1, 128 kDa	yes
P49418-2	2, 108 kDa

RefSeq proteins (2): NP_001626, NP_647477 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR003005	Amphiphysin	Family
IPR003017	Amphiphysin_1	Family
IPR004148	BAR_dom	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR035470	Amphiphysin_I_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF03114

UniProt features (30 total): modified residue 9, helix 9, sequence variant 3, domain 2, region of interest 2, coiled-coil region 2, chain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
4ATM	Crystal structure of the BAR domain of human Amphiphysin, isoform 1 at 1.8 Angstrom …	X-RAY DIFFRACTION	1.78
5M61	Clathrin heavy chain N-terminal domain bound to an extended amphiphysin clathrin-box motif	X-RAY DIFFRACTION	1.84
5M5S	Clathrin heavy chain N-terminal domain bound to amphiphysin clathrin-box motif	X-RAY DIFFRACTION	1.88
1KY7	THE AP-2 CLATHRIN ADAPTOR ALPHA-APPENDAGE IN COMPLEX WITH AMPHIPHYSIN FXDXF	X-RAY DIFFRACTION	2.15
1UTC	Clathrin terminal domain complexed with TLPWDLWTT	X-RAY DIFFRACTION	2.3
3SOG	Crystal structure of the BAR domain of human Amphiphysin, isoform 1	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49418-F1	64.84	0.39

Human Protein Atlas

Protein class: Predicted intracellular proteins, Cancer-related genes, Mutational cancer driver genes

Protein evidence: Evidence at protein level

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

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

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

Post-translational modifications (9)

Type	Positions
Phosphoserine	262, 268, 272, 276, 506, 638, 252
Phosphothreonine	280, 260

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-8856828	Clathrin-mediated endocytosis	curated
R-HSA-199991	Membrane Trafficking	—
R-HSA-5653656	Vesicle-mediated transport	—

MSigDB gene sets: 176 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, BENPORATH_ES_WITH_H3K27ME3, MODULE_274, AP4_Q6, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01, REACTOME_MEMBRANE_TRAFFICKING, CAGCTG_AP4_Q5, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_CELL_CELL_SIGNALING, MODULE_66, MODULE_381, DACOSTA_UV_RESPONSE_VIA_ERCC3_TTD_DN

GO Biological Process (3): endocytosis (GO:0006897), chemical synaptic transmission (GO:0007268), synaptic vesicle endocytosis (GO:0048488)

GO Molecular Function (2): phospholipid binding (GO:0005543), protein binding (GO:0005515)

GO Cellular Component (9): cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), actin cytoskeleton (GO:0015629), synaptic vesicle membrane (GO:0030672), leading edge membrane (GO:0031256), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Membrane Trafficking	1
Vesicle-mediated transport	1

GO top-level categories

22 GO namespaces:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
anterograde trans-synaptic signaling	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
lipid binding	1
binding	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
cytoskeleton	1
synaptic vesicle	1
exocytic vesicle membrane	1
plasma membrane	1
cell leading edge	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
leading edge membrane	CC	direct assay
phospholipid binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,026 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMPH	SYNJ1	O43426	935
AMPH	DPYSL5	Q9BPU6	882
AMPH	PNMA2	Q9UL42	882
AMPH	LGI1	O95970	881
AMPH	SYNJ2	O15056	877
AMPH	GAD2	Q05329	855
AMPH	SH3GL2	Q99962	839
AMPH	DNM2	P50570	819
AMPH	ZIC4	Q8N9L1	818
AMPH	DNER	Q8NFT8	812
AMPH	EPS15	P42566	806
AMPH	SNX9	Q9Y5X1	802
AMPH	CNTNAP2	Q9UHC6	800
AMPH	DNM1	Q05193	796
AMPH	SNX1	Q13596	786

IntAct

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

17 partners by confidence:

Partner	Interaction type	MIscore	Records
DNM1	direct interaction	0.820	6
ARL16	physical association	0.780	7
BIN1	association	0.740	6
DNM2	association	0.710	3
SYNJ1	direct interaction	0.670	4
ATN1	physical association	0.560	3
DEUP1	physical association	0.560	3
PPP3CA	physical association	0.560	3
PPP3CC	physical association	0.560	3
CLIP4	association	0.530	2
EGFR	physical association	0.510	2
TERF1	physical association	0.510	2
MAPK6	physical association	0.370	1
PROP1	physical association	0.370	1
DNM3	association	0.350	1
CEP63	physical association	0.000	1
RIN3	physical association	0.000	1

BioGRID (116 interactions; top human partners by supporting records): DNM1 (Reconstituted Complex; 10 records), BIN1 (Affinity Capture-MS; 5 records), AP1B1 (Affinity Capture-MS; 3 records), AP2A1 (Affinity Capture-MS; 3 records), AP2A2 (Affinity Capture-MS; 3 records), AP2B1 (Affinity Capture-MS; 3 records), CDK5R1 (Affinity Capture-Western; 3 records), PLD1 (Phenotypic Suppression; 3 records), PLD2 (Phenotypic Suppression; 3 records), SYNJ1 (Reconstituted Complex; 3 records), SYNM (Affinity Capture-Western; 3 records), TP73 (Two-hybrid; 3 records), AAGAB (Affinity Capture-MS; 2 records), AP2M1 (Affinity Capture-MS; 2 records), AP2S1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

showing 12 of 23 signaling interactions:

A	Effect	B	Mechanism
DYRK1A	down-regulates	AMPH	phosphorylation
MAPK1	“down-regulates activity”	AMPH	phosphorylation
MAPK1	down-regulates	AMPH	phosphorylation
MAPK3	“down-regulates activity”	AMPH	phosphorylation
MAPK3	down-regulates	AMPH	phosphorylation
DYRK1A	“down-regulates activity”	AMPH	phosphorylation
CSNK2A1	down-regulates	AMPH	phosphorylation
Gbeta	down-regulates	AMPH	phosphorylation
ERK1/2	down-regulates	AMPH	phosphorylation
CDKL5	“down-regulates activity”	AMPH	phosphorylation
CyclinB/CDK1	unknown	AMPH	phosphorylation
CDK5	unknown	AMPH	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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
Clathrin-mediated endocytosis	6	39.3×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	5	29.8×	5e-05

Disease & clinical

Genetic variants

Variant evidence for AMPH: 119 ClinVar records (5 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	81
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (5)

Showing all 5 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
3062975	GRCh37/hg19 7p14.1(chr7:38484106-42786613)x1	Pathogenic	criteria provided, single submitter	1
4851062	GRCh37/hg19 7p14.2-13(chr7:36499426-43428961)x1	Pathogenic	criteria provided, single submitter	1
3062981	GRCh37/hg19 7p14.3-14.1(chr7:33478398-39686397)x1	Likely pathogenic	criteria provided, single submitter	1
149132	GRCh38/hg38 7p14.2-14.1(chr7:35460776-42013800)x1	Pathogenic	no assertion criteria provided	1
442557	GRCh37/hg19 7p14.1(chr7:38619347-40542932)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore AMPH’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; 35 predictions of 2,800):

Position(s)	Effect	Δscore	Sites
7:38389802–38389803	donor_loss	1.0000	5
7:38389906–38389907	acceptor_loss	1.0000	5
7:38391746–38391747	donor_loss	1.0000	3
7:38391786	donor_gain	1.0000
7:38394003–38394004	donor_loss	1.0000	4
7:38436270–38436271	donor_loss	1.0000	6
7:38436389–38436390	acceptor_loss	1.0000	6
7:38436399	acceptor_gain	1.0000
7:38436403	acceptor_gain	1.0000
7:38461281–38461282	donor_loss	1.0000	3

AlphaMissense

1,974 missense substitutions predicted likely pathogenic (of 4,515 scored), across 400 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
M70	9	0.976	0.999
M231	9	0.891	0.998
D144	8	0.999	1.000
D146	8	0.999	1.000
H150	8	0.998	1.000
D36	8	0.997	1.000
F39	8	0.996	1.000
D115	8	0.996	0.999
F216	8	0.995	1.000
F46	8	0.993	1.000
F128	8	0.993	1.000
H110	8	0.990	1.000
D122	8	0.990	0.999
D108	8	0.986	0.998
F686	8	0.986	1.000
F9	8	0.982	0.999
F180	8	0.980	1.000
F243	8	0.980	0.999
D32	8	0.979	0.997
F109	8	0.975	1.000

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Glioblastoma Multiforme)

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	0.000477

Disease associations

OMIM: gene MIM:600418 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST007844_14	Ankylosing spondylitis	1e-6
GCST008524_20	Bitter non-alcoholic beverage consumption	4e-6
GCST003262_928	Post bronchodilator FEV1	5e-6
GCST008275_5	Cerebral microbleeds	6e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0010059	cerebral microbleeds
EFO:0010093	bitter non-alcoholic beverage consumption measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

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

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs12701634		Other	Genotype CC is associated with increased transcription of ABCB1 as compared to genotypes CT + TT.	PMID:28601971

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
bisphenol A	affects cotreatment, decreases expression, increases methylation	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
tert-Butylhydroperoxide	decreases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
terbufos	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	decreases expression	1
Heroin	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Hydrogen Peroxide	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3K2	N/Tert-1 AMPH	Telomerase immortalized cell line	Male
CVCL_D8Z4	Ubigene HEK293 AMPH KO	Transformed cell line	Female

Clinical trials (associated diseases)

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