SH3BP1

Chr 22

SH3 domain binding protein 1

Also known as: ARHGAP43

NCBI Gene: 23616 ENSG00000100092 UniProt: Q9Y3L3 OMIM: 617368

The protein functions as a GTPase activating protein that specifically inactivates RAC1 and CDC42, regulating actin cytoskeleton dynamics, cell migration, epithelial junction formation, and angiogenesis. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, developmental delay, and dysmorphic features. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.54), suggesting some tolerance to protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the Rho GTPase activating protein (RhoGAP) family. The encoded protein regulates Rac signaling and plays a role in cytoskeletal dynamics, cell motility and epithelial junction formation. This protein's association with the exocyst complex, which tethers secretory vesicles to the plasma membrane, has been demonstrated to be important in cell motility. In a distinct complex, this protein has been shown to regulate epithelial junction formation and morphogenesis. By interacting with the Plexin-D1 cell surface receptor, this protein mediates changes in the cytoskeleton in response to semaphorin binding. This protein may promote metastasis in human liver cancer cells and tissues. [provided by RefSeq, Mar 2017]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.54

Clinical Summary— SH3BP1

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

📋

ClinVar Variants

119 VUS of 153 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.010

Z-score 3.45

OE 0.31 (0.19–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.58Z-score

OE missense 0.78 (0.71–0.85)

305 obs / 393.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.19–0.54)

0≤0.351.4

Missense OE?0.78 (0.71–0.85)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 9 / 29.1Missense obs/exp: 305 / 393.0Syn Z: -0.24

This gene — mechanism propensity

0.6064th %ile

GOF

0.6444th %ile

LOF

0.3842th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

153 submitted variants in ClinVar

ClinVar

Classification Summary

VUS119

Likely Benign4

Benign2

119

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	119	0	0	119
Likely Benign	2	1	1	4
Benign	0	1	1	2
Total	121	2	2	125

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap SH3BP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →