SH3RF2

Summary

SH3RF2 (SH3 domain containing ring finger 2, HGNC:26299) is a protein-coding gene on chromosome 5q32, encoding E3 ubiquitin-protein ligase SH3RF2 (Q8TEC5). Has E3 ubiquitin-protein ligase activity.

Enables protein phosphatase 1 binding activity and ubiquitin protein ligase activity. Involved in several processes, including positive regulation of JNK cascade; protein autoubiquitination; and regulation of protein metabolic process. Located in nucleoplasm.

Source: NCBI Gene 153769 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 151 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.90 (unconstrained)
• MANE Select transcript: NM_152550
• Notable: 151 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26299
Approved symbol	SH3RF2
Name	SH3 domain containing ring finger 2
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23654, RNF158, Hepp1, POSHER
Ensembl gene	ENSG00000156463
Ensembl biotype	protein_coding
OMIM	613377
Entrez	153769

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000359120

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

ENST00000359120, ENST00000503848, ENST00000504522, ENST00000506591, ENST00000509286, ENST00000511217, ENST00000511705, ENST00000859824, ENST00000859825, ENST00000859826, ENST00000859827, ENST00000859828, ENST00000859829, ENST00000859830, ENST00000859831, ENST00000859832, ENST00000859833, ENST00000930066, ENST00001109506, ENST00001109507, ENST00001109508, ENST00001109509, ENST00001114395, ENST00001122446, ENST00001132404

RefSeq mRNA: 1 — MANE Select: NM_152550 NM_152550

CCDS: CCDS4280

Canonical transcript exons

ENST00000359120 — 10 exons

Exon	Start	End
ENSE00001202540	146013747	146014061
ENSE00001202547	146000058	146000327
ENSE00001406919	146062426	146063292
ENSE00001414856	145937823	145938306
ENSE00001518493	145936578	145936694
ENSE00002290081	146049075	146049245
ENSE00002451839	146055981	146056213
ENSE00002496161	146004058	146004153
ENSE00003610869	146047772	146047863
ENSE00003690580	146059866	146060224

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5613 / max 1024.7791, expressed in 1098 samples.

Highest expression (Bgee): ventricle myocardium, apex of heart, heart right ventricle, testis, myocardium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SH3RF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adrenal Gland	eqtl	2.9e-23	-0.90	5:145939091:A:T
Muscle Skeletal	sqtl	2.9e-12	+0.41	5:146065187:G:C
Artery Aorta	eqtl	1.7e-10	+0.58	5:145977091:G:A
Thyroid	eqtl	4.4e-10	+0.23	5:146019241:C:G
Heart Left Ventricle	eqtl	1.4e-06	+0.12	5:146067779:GCCCACA:G
Pancreas	eqtl	2.5e-06	+0.30	5:145979152:A:C
Skin Sun Exposed Lower leg	eqtl	4.7e-06	+0.10	5:146054200:C:T
Artery Tibial	eqtl	2.0e-05	+0.66	5:145976640:G:T
Esophagus Mucosa	eqtl	1.4e-04	-0.16	5:145933142:C:T
Brain Nucleus accumbens basal ganglia	eqtl	1.4e-03	+0.21	5:145457246:G:A
Adipose Subcutaneous	sqtl	5.5e-03	-1.11	5:146304587:G:A
Colon Transverse	sqtl	9.0e-03	+0.74	5:145632307:G:A
Adipose Subcutaneous	eqtl	1.5e-02	+0.19	5:145933142:C:T
Stomach	eqtl	1.5e-02	+0.31	5:145075901:A:T
Breast Mammary Tissue	sqtl	1.6e-02	-1.08	5:145662091:T:G
Colon Transverse	eqtl	1.6e-02	+0.35	5:146745371:G:T
Artery Coronary	eqtl	1.9e-02	+0.27	5:146109598:T:C
Testis	sqtl	2.7e-02	+0.54	5:146143773:T:G
Esophagus Muscularis	eqtl	2.8e-02	+0.52	5:145928057:A:G
Breast Mammary Tissue	eqtl	2.8e-02	+0.47	5:146549342:G:A

FANTOM5 promoters

showing 10 of 13 alternative TSS:

Promoter ID	TPM avg	Samples expressed
59191	4.0114	958
59206	2.0041	53
59194	1.9785	458
59205	0.8975	41
59203	0.6537	4
59192	0.3243	174
59209	0.2147	12
59195	0.1863	100
59193	0.1546	90
59208	0.0664	9

Top tissues by expression

showing 100 of 249 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.48	gold quality
apex of heart	UBERON:0002098	99.42	gold quality
heart right ventricle	UBERON:0002080	99.21	gold quality
left testis	UBERON:0004533	99.18	gold quality
right testis	UBERON:0004534	98.99	gold quality
myocardium	UBERON:0002349	98.96	gold quality
sperm	CL:0000019	98.86	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.71	gold quality
upper arm skin	UBERON:0004263	98.54	gold quality
heart left ventricle	UBERON:0002084	98.53	gold quality
cardiac ventricle	UBERON:0002082	98.52	gold quality
oviduct epithelium	UBERON:0004804	98.42	gold quality
right atrium auricular region	UBERON:0006631	98.08	gold quality
cardiac atrium	UBERON:0002081	97.96	gold quality
lower esophagus mucosa	UBERON:0035834	96.94	gold quality
adult organism	UBERON:0007023	96.93	gold quality
testis	UBERON:0000473	96.55	gold quality
upper leg skin	UBERON:0004262	95.87	gold quality
heart	UBERON:0000948	95.51	gold quality
skin of abdomen	UBERON:0001416	95.35	gold quality
gingival epithelium	UBERON:0001949	95.23	gold quality
skin of leg	UBERON:0001511	95.19	gold quality
zone of skin	UBERON:0000014	94.75	gold quality
pancreatic ductal cell	CL:0002079	94.61	gold quality
skin of hip	UBERON:0001554	94.47	gold quality
esophagus mucosa	UBERON:0002469	94.10	gold quality
gingiva	UBERON:0001828	93.53	gold quality
gastrocnemius	UBERON:0001388	91.55	gold quality
mammalian vulva	UBERON:0000997	90.72	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.54	gold quality
esophagus squamous epithelium	UBERON:0006920	90.17	gold quality
epithelial cell of pancreas	CL:0000083	89.99	gold quality
muscle of leg	UBERON:0001383	89.96	gold quality
mucosa of transverse colon	UBERON:0004991	89.57	gold quality
vagina	UBERON:0000996	88.91	gold quality
rectum	UBERON:0001052	88.55	gold quality
ileal mucosa	UBERON:0000331	88.27	gold quality
body of pancreas	UBERON:0001150	87.25	gold quality
gall bladder	UBERON:0002110	87.09	gold quality
oral cavity	UBERON:0000167	86.94	gold quality
nipple	UBERON:0002030	86.65	gold quality
mouth mucosa	UBERON:0003729	86.53	gold quality
duodenum	UBERON:0002114	86.42	gold quality
body of stomach	UBERON:0001161	86.30	gold quality
penis	UBERON:0000989	86.23	gold quality
minor salivary gland	UBERON:0001830	85.98	gold quality
jejunal mucosa	UBERON:0000399	85.45	gold quality
colonic mucosa	UBERON:0000317	85.42	gold quality
stomach	UBERON:0000945	85.15	gold quality
saliva-secreting gland	UBERON:0001044	84.83	gold quality
transverse colon	UBERON:0001157	84.59	gold quality
right lobe of liver	UBERON:0001114	84.57	gold quality
right uterine tube	UBERON:0001302	84.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.04	gold quality
quadriceps femoris	UBERON:0001377	83.92	silver quality
muscle tissue	UBERON:0002385	83.82	gold quality
vastus lateralis	UBERON:0001379	83.66	silver quality
right lobe of thyroid gland	UBERON:0001119	83.47	gold quality
skeletal muscle tissue	UBERON:0001134	83.36	gold quality
pharyngeal mucosa	UBERON:0000355	83.35	gold quality
deltoid	UBERON:0001476	83.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.85	gold quality
left lobe of thyroid gland	UBERON:0001120	82.02	gold quality
tonsil	UBERON:0002372	81.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.60	gold quality
pancreas	UBERON:0001264	81.55	gold quality
thyroid gland	UBERON:0002046	81.32	gold quality
small intestine	UBERON:0002108	81.20	gold quality
fallopian tube	UBERON:0003889	80.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.80	silver quality
parotid gland	UBERON:0001831	79.53	gold quality
esophagus	UBERON:0001043	79.31	gold quality
tibialis anterior	UBERON:0001385	79.12	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	78.82	gold quality
colonic epithelium	UBERON:0000397	78.80	gold quality
palpebral conjunctiva	UBERON:0001812	78.75	gold quality
fundus of stomach	UBERON:0001160	78.72	gold quality
biceps brachii	UBERON:0001507	78.66	silver quality
intestine	UBERON:0000160	78.30	gold quality
germinal epithelium of ovary	UBERON:0001304	77.91	gold quality
jejunum	UBERON:0002115	77.39	gold quality
ascending aorta	UBERON:0001496	77.28	gold quality
large intestine	UBERON:0000059	77.24	gold quality
thoracic aorta	UBERON:0001515	77.22	gold quality
colon	UBERON:0001155	76.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.50	gold quality
descending thoracic aorta	UBERON:0002345	75.96	gold quality
nasal cavity epithelium	UBERON:0005384	75.93	silver quality
nasal cavity mucosa	UBERON:0001826	75.62	gold quality
upper lobe of left lung	UBERON:0008952	75.47	gold quality
liver	UBERON:0002107	75.35	gold quality
nucleus accumbens	UBERON:0001882	75.33	gold quality
vena cava	UBERON:0004087	75.19	gold quality
right coronary artery	UBERON:0001625	74.83	gold quality
left coronary artery	UBERON:0001626	74.62	gold quality
upper lobe of lung	UBERON:0008948	74.58	gold quality
caudate nucleus	UBERON:0001873	74.24	gold quality
coronary artery	UBERON:0001621	74.03	gold quality
aorta	UBERON:0000947	73.83	gold quality
pylorus	UBERON:0001166	73.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	32.87
E-ANND-3	yes	7.36

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skin 1	tissue	53.6	not detected
Heart muscle	tissue	37.3	low
Caudate putamen	tissue	26.7
Skeletal muscle	tissue	21.3	not detected
Esophagus	tissue	20.7	not detected
Vagina	tissue	19.7	not detected
Stomach 1	tissue	19.3	low
Duodenum	tissue	15.0	low
Nucleus accumbens	tissue	13.6
Rectum	tissue	13.4	low
Colon	tissue	13.4	low
Pancreas	tissue	13.0	low
Small intestine	tissue	12.9	low
Putamen	tissue	12.7
Salivary gland	tissue	11.4	medium
Gallbladder	tissue	11.2	medium
Basal ganglia	tissue	10.9	low
Tongue	tissue	8.2
Tonsil	tissue	7.2	medium
Thyroid gland	tissue	5.9	low
Fallopian tube	tissue	5.8	low
Ventral forebrain	tissue	4.7
Liver	tissue	4.5	low
Spinal cord	tissue	4.5
Breast	tissue	4.4	low
Testis	tissue	4.3	medium
Medulla oblongata	tissue	3.6
Epididymis	tissue	3.4	low
Cervix	tissue	3.1	low
Pons	tissue	2.6
Postcentral gyrus	tissue	2.3
Appendix	tissue	2.3	low
Substantia nigra	tissue	2.2
Lung	tissue	2.2	not detected
Prostate	tissue	2.2	low
Superior colliculi	tissue	2.1
Adipose tissue	tissue	1.7	not detected
Septum	tissue	1.7
Cerebral cortex	tissue	1.6	medium
Choroid plexus	tissue	1.6
Thalamus	tissue	1.6
Insular cortex	tissue	1.6
Pituitary gland	tissue	1.5
Midbrain	tissue	1.5
Hypothalamus	tissue	1.5
Hippocampal formation	tissue	1.5
Entorhinal cortex	tissue	1.4
Motor cortex	tissue	1.2
Retrosplenial and cingulate cortex	tissue	1.2
Periaqueductal gray	tissue	1.2
Retrosplenial cortex	tissue	1.2
Temporal cortex	tissue	1.2
Occipital cortex	tissue	1.2
Prefrontal cortex	tissue	1.1
Amygdala	tissue	1.1
Somatosensory cortex	tissue	1.1
Smooth muscle	tissue	1.0	not detected
Endometrium 1	tissue	1.0	low
Thymus	tissue	0.9
Urinary bladder	tissue	0.8	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Caudate nucleus (13.6), Temporo-occipital transitional zone (10.1), Area parastriata, superior (6.4), Area striata (6.2), Transversal temporal gyrus, anterior (6.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting SH3RF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

30 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-5572	98.55	65.84	970
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-1306-5P	97.11	64.04	755
HSA-MIR-3974	96.56	66.22	928
HSA-MIR-597-3P	96.46	68.03	1035
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-885-3P	95.14	63.08	448
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1185-5P	94.47	65.95	725
HSA-MIR-12115	94.19	66.37	738
HSA-MIR-3677-5P	93.16	64.62	393

Functional genomics

gnomAD constraint: pLI 1.68e-09, LOEUF 0.897, missense Z 0.544 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000359120 — one region, missense o/e 0.99.

Literature-anchored findings (GeneRIF, showing 4)

• the novel protein heart protein phosphatase 1-binding protein (Hepp1), encoded by FLJ23654, was identified.Hepp1 can play a role in cardiac functions by working in concert with PP1. (PMID:19945436)
• Assessing the role of SH3RF1 and SH3RF2 polymorphisms in susceptibility to tuberculosis: A case-control study in the Han Chinese population. (PMID:33129950)
• Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD. (PMID:33894019)
• SH3RF2 contributes to cisplatin resistance in ovarian cancer cells by promoting RBPMS degradation. (PMID:38195842)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sh3rf2	ENSMUSG00000057719
rattus_norvegicus	Sh3rf2	ENSRNOG00000018780
drosophila_melanogaster	Dlish	FBGN0034264
drosophila_melanogaster	EndoB	FBGN0034433
caenorhabditis_elegans		WBGENE00001335
caenorhabditis_elegans		WBGENE00012891
caenorhabditis_elegans		WBGENE00015128

Paralogs (12): SORBS1 (ENSG00000095637), SH3GLB1 (ENSG00000097033), NCF4 (ENSG00000100365), SH3GL2 (ENSG00000107295), SH3D19 (ENSG00000109686), SORBS3 (ENSG00000120896), SH3GL3 (ENSG00000140600), SH3GL1 (ENSG00000141985), SH3GLB2 (ENSG00000148341), SH3RF1 (ENSG00000154447), SORBS2 (ENSG00000154556), SH3RF3 (ENSG00000172985)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2444628) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal hippocampus morphology	1
abnormal social investigation	1
hyperactivity	1
increased stereotypic behavior	1
abnormal nest building behavior	1
postnatal growth retardation	1
seizures	1
abnormal nervous system electrophysiology	1
increased vertical activity	1
abnormal afterhyperpolarization	1
abnormal miniature excitatory postsynaptic currents	1
abnormal dendritic spine morphology	1
postnatal lethality, incomplete penetrance	1
prenatal lethality, incomplete penetrance	1
abnormal hippocampal pyramidal neuron dendrite morphology	1
decreased vocalization	1
abnormal response to social novelty	1
increased dendritic spine density	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
Saccharomyces cerevisiae YJM789	A7A261	100.0%	Diamond
Saccharomyces cerevisiae S288C	P43603	100.0%	Diamond
Drosophila erecta	Q8I1I3	100.0%	Diamond
Pongo abelii	Q5RBR0	99.0%	Diamond
Drosophila willistoni	Q8I1A6	98.9%	Diamond
Drosophila virilis	Q8I190	98.4%	Diamond
Drosophila pseudoobscura pseudoobscura	Q8I1C0	98.4%	Diamond
Bos taurus	Q2KJA1	97.0%	Diamond
Gallus gallus	Q8AXV0	91.3%	Diamond
Xenopus tropicalis	Q28E95	87.5%	Diamond
Xenopus laevis	Q6NRD3	87.5%	Diamond
Danio rerio	Q7T2D0	78.3%	Diamond
Debaryomyces hansenii CBS767	Q6BNP6	57.7%	Diamond
Candida albicans SC5314	Q5A895	57.5%	Diamond
Scheffersomyces stipitis CBS 6054	A3LXQ8	51.6%	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
RBM27-POU4F3	protein-coding	127814297
PLAC8L1	protein-coding	153770
LARS1	protein-coding	51520
RBM27	protein-coding	54439
PRELID2	protein-coding	153768
GRXCR2	protein-coding	643226
POU4F3	protein-coding	5459

Protein

Protein identifiers

E3 ubiquitin-protein ligase SH3RF2 — Q8TEC5 (reviewed: Q8TEC5)

Alternative names: Heart protein phosphatase 1-binding protein, POSH-eliminating RING protein, Protein phosphatase 1 regulatory subunit 39, RING finger protein 158, RING-type E3 ubiquitin transferase SH3RF2, SH3 domain-containing RING finger protein 2

All UniProt accessions (1): Q8TEC5

UniProt curated annotations — full annotation on UniProt →

Function. Has E3 ubiquitin-protein ligase activity. Acts as an anti-apoptotic regulator of the JNK pathway by ubiquitinating and promoting the degradation of SH3RF1, a scaffold protein that is required for pro-apoptotic JNK activation. Facilitates TNF-mediated recruitment of adapter proteins TRADD and RIPK1 to TNFRSF1A and regulates PAK4 protein stability via inhibition of its ubiquitin-mediated proteasomal degradation. Inhibits PPP1CA phosphatase activity.

Subunit / interactions. Interacts with FASLG and PPP1CA. Interacts with PAK4 and TNFRSF1A. Interacts with DLK1, MAP3K10/MLK2, MAPK8IP1/JIP1, MAPK8IP2/JIP2 and MAPK8IP3/JIP3. Interacts with RAC1 (both active GTP- or inactive GDP-bound forms).

Subcellular location. Nucleus.

Tissue specificity. Heart (at protein level). Up-regulated in colon cancer tissues as compared to normal colon tissues (at protein level). Testis. In the heart, present in the apex, left atrium, right atrium, left ventricle and right ventricle, but not in the aorta.

Post-translational modifications. Autoubiquitinated.

Domain organisation. The RING finger domain is required for ubiquitin ligase activity and autoubiquitination.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the SH3RF family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TEC5-1	1	yes
Q8TEC5-2	2
Q8TEC5-3	3

RefSeq proteins (1): NP_689763* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR028511	SH3RF2_RING-HC_Zfn	Domain
IPR035792	SH3RF2_SH3_1	Domain
IPR035794	SH3RF2_SH3_2	Domain
IPR035822	SH3RF2_SH3_3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR050384	Endophilin_SH3RF	Family

Pfam: PF00018, PF07653, PF13639, PF14604

UniProt features (28 total): sequence variant 7, region of interest 6, domain 3, splice variant 3, compositionally biased region 2, mutagenesis site 2, sequence conflict 2, chain 1, modified residue 1, zinc finger region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEC5-F1	57.92	0.22

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH uncertain · 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.

Post-translational modifications (1)

Type	Positions
Phosphoserine	649

Mutagenesis-validated functional residues (2)

Position	Phenotype
643	significant loss of interaction with ppp1ca. significant loss of interaction with ppp1ca; when associated with g-645.
645	significant loss of interaction with ppp1ca. significant loss of interaction with ppp1ca; when associated with g-643.

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 142 (showing top): AP1_01, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TGACCTY_ERR1_Q2, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, TCF4_Q5, AP1_Q4_01, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_JNK_CASCADE, GOBP_PROTEIN_AUTOUBIQUITINATION, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (9): positive regulation of cell migration (GO:0030335), negative regulation of protein ubiquitination (GO:0031397), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of apoptotic process (GO:0043066), negative regulation of JNK cascade (GO:0046329), positive regulation of JNK cascade (GO:0046330), protein autoubiquitination (GO:0051865), protein ubiquitination (GO:0016567), regulation of JNK cascade (GO:0046328)

GO Molecular Function (8): protein phosphatase inhibitor activity (GO:0004864), protein phosphatase 1 binding (GO:0008157), zinc ion binding (GO:0008270), phosphatase binding (GO:0019902), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

33 GO namespaces:

Category	Terms
JNK cascade	3
protein ubiquitination	2
regulation of JNK cascade	2
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of MAPK cascade	1
positive regulation of MAPK cascade	1
protein modification by small protein conjugation	1
regulation of MAPK cascade	1
phosphoprotein phosphatase activity	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
protein phosphatase binding	1
transition metal ion binding	1
enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	mutant phenotype
negative regulation of protein ubiquitination	BP	mutant phenotype
positive regulation of JNK cascade	BP	mutant phenotype
positive regulation of cell migration	BP	mutant phenotype
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	BP	mutant phenotype
protein autoubiquitination	BP	mutant phenotype
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
phosphatase binding	MF	direct assay
protein phosphatase 1 binding	MF	direct assay
ubiquitin protein ligase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 688 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3RF2	TSHR	P16473	554
SH3RF2	SOCS2	O14508	552
SH3RF2	SSBP1	Q04837	487
SH3RF2	ARMCX4	Q5H9R4	473
SH3RF2	ANKRD9	Q96BM1	456
SH3RF2	COMMD5	Q9GZQ3	449
SH3RF2	UHRF2	Q96PU4	448
SH3RF2	TRAPPC12	Q8WVT3	448
SH3RF2	LRP5	O75197	428
SH3RF2	GHR	P10912	428
SH3RF2	SP7	Q8TDD2	427
SH3RF2	OR5I1	Q13606	400
SH3RF2	CISH	Q9NSE2	388
SH3RF2	GPR151	Q8TDV0	385
SH3RF2	PRELID2	Q8N945	376

IntAct

Human interaction partners of SH3RF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

20 partners by confidence:

Partner	Interaction type	MIscore	Records
MTUS2	physical association	0.670	5
AMOTL2	physical association	0.670	4
GOLGA2	physical association	0.670	4
PPP1CA	physical association	0.660	3
BANP	physical association	0.560	4
AKAP8L	physical association	0.560	3
BAG4	physical association	0.560	3
CCDC102B	physical association	0.560	3
CYSRT1	physical association	0.560	3
EFS	physical association	0.560	3
NEK6	physical association	0.560	3
VPS37C	physical association	0.560	3
ENG	direct interaction	0.440	1
FASLG	direct interaction	0.440	1
HSP90AB1	physical association	0.400	1
SIAH1	physical association	0.400	1
ZYG11B	physical association	0.400	1
PPP1CC	physical association	0.370	2
RBPMS	physical association	0.370	1
UBE2N	physical association	0.370	1

BioGRID (68 interactions; top human partners by supporting records): PAK4 (Affinity Capture-MS; 4 records), PPP1CA (Two-hybrid; 3 records), RBPMS (Two-hybrid; 3 records), AMOTL2 (Two-hybrid; 2 records), ECHS1 (Affinity Capture-MS; 2 records), GOLGA2 (Two-hybrid; 2 records), HOMEZ (Two-hybrid; 2 records), LZTS2 (Two-hybrid; 2 records), MTUS2 (Two-hybrid; 2 records), PPP1CC (Two-hybrid; 2 records), SH3RF1 (Affinity Capture-Western; 2 records), AKAP8L (Two-hybrid), APP (Reconstituted Complex), ATXN7L2 (Two-hybrid), BAG4 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	SH3RF2	ubiquitination

Disease & clinical

Genetic variants

Variant evidence for SH3RF2: 151 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	133
Likely benign	6
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,111):

Position(s)	Effect	Δscore	Sites
5:146000056–146000057	acceptor_loss	1.0000	2
5:146000328–146000329	donor_loss	1.0000	4
5:145936695–145936696	donor_loss	0.9900	5
5:146000056–146000057	acceptor_loss	0.9900	3
5:146000285	donor_gain	0.9900
5:146000328	donor_loss	0.9900
5:146047864–146047865	donor_loss	0.9900	4
5:146049073–146049074	acceptor_loss	0.9900	6
5:146049202	donor_gain	0.9900
5:146049246–146049247	donor_loss	0.9900	5

AlphaMissense

791 missense substitutions predicted likely pathogenic (of 4,725 scored), across 218 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
H30	8	0.987	0.995
F32	8	0.972	0.999
F214	8	0.965	0.997
F645	8	0.958	0.997
F242	8	0.950	0.996
N66	8	0.912	0.995
F198	8	0.912	0.987
C33	7	0.996	0.998
C12	7	0.994	0.999
C15	7	0.994	0.998
C49	7	0.993	0.998
C36	7	0.992	0.996
C28	7	0.990	0.997
W230	7	0.990	0.998
C52	7	0.989	0.996
F246	7	0.971	0.990
D227	7	0.931	0.987
F146	7	0.878	0.987
I625	7	0.851	0.995
D150	7	0.794	0.941

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:613377 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST010796_3071	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-8
GCST010796_3072	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-8
GCST009173_1	Response to (pegylated) interferon in HBeAG-positive hepatitis B	3e-6
GCST003650_8	Bacteremia	4e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007859	response to interferon
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
pirinixic acid	increases activity, affects binding, decreases expression	1
lead acetate	decreases expression	1
beta-lapachone	increases expression	1
zinc chromate	increases abundance, decreases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
abrine	increases expression	1
Temozolomide	decreases expression	1
Decitabine	decreases expression, affects reaction	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Cytarabine	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression, affects response to substance	1
Phthalic Acids	increases methylation	1
Progesterone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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

showing 60 of 210 trials:

NCT	Phase	Status	Title
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	Phase 3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	Phase 3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	Phase 3	RECRUITING	Reducing Missed Appointments
NCT07377032	Phase 3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	Phase 2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	Phase 2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	Phase 1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	Phase 1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	Phase 1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	Phase 2/3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	Phase 2/3	COMPLETED	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	Early Phase 1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	COMPLETED	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice
NCT03381027	Not specified	COMPLETED	BABY SMART (Study of Massage Therapy, Sleep And neurodevelopMenT)
NCT03388294	Not specified	COMPLETED	Evaluation of a Novel Intervention for Infants At Risk for Neurodevelopmental Disorders
NCT03410810	Not specified	UNKNOWN	Childhood Outcomes of Preterm Brain Abnormalities
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
NCT03577756	Not specified	COMPLETED	Neurodevelopmental Assessment of Infants With Cystic Fibrosis
NCT03654248	Not specified	COMPLETED	Let’s Get Organized in Adult Psychiatric/habilitation Care
NCT03659279	Not specified	COMPLETED	Let’s Get Organized Feasibility Study
NCT03722615	Not specified	COMPLETED	Epidemiology of Congenital Cytomegalovirus in a High HIV Prevalence Setting, South Africa
NCT03770832	Not specified	ACTIVE_NOT_RECRUITING	Wearable Sensors and Video Recordings to Monitor Motor Development
NCT03830879	Not specified	RECRUITING	Shenzhen Birth Cohort Study
NCT03835689	Not specified	COMPLETED	Strongest FamiliesTM Neurodevelopmental
NCT03882788	Not specified	COMPLETED	The Effect of Anesthesia on Neurodevelopmental Outcome (NDO)
NCT03922087	Not specified	COMPLETED	No-worry Baby Project
NCT03977259	Not specified	ACTIVE_NOT_RECRUITING	Targeting Human Milk Fortification to Improve Preterm Infant Growth and Brain Development
NCT04043572	Not specified	UNKNOWN	The Biomarkers of Neurological Disease in Utero Study
NCT04096430	Not specified	RECRUITING	Evaluation of Effectiveness of Child-oriented Goal-setting in Paediatric Rehabilitation (the ENGAGE Approach)
NCT04108273	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children
NCT04201509	Not specified	COMPLETED	Validity of Neurocognitive Assessment Methods in Childhood ADHD
NCT04233775	Not specified	UNKNOWN	Altered Cerebral Growth and Development in Infants With Congenital Heart Disease
NCT04313283	Not specified	COMPLETED	Translating Peer-to-Peer Support Into a Clinical Setting