SH3BP5L

Chr 1

SH3 binding domain protein 5 like

NCBI Gene: 80851 ENSG00000175137 UniProt: Q7L8J4 OMIM: 620652

The SH3BP5L protein functions as a guanine nucleotide exchange factor for RAB11A and is involved in intracellular signal transduction in the cytoplasm. Mutations in this gene cause autosomal recessive neurodevelopmental disorder with epilepsy and brain atrophy. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.596), and the associated disorder involves the nervous system with seizures and structural brain abnormalities.

OMIM ResearchSummary from RefSeq, UniProt

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in intracellular signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— SH3BP5L

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

47 VUS of 57 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?

0.60LOEUF

pLI 0.046

Z-score 2.89

OE 0.30 (0.16–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.68Z-score

OE missense 0.71 (0.63–0.80)

189 obs / 266.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.16–0.60)

0≤0.351.4

Missense OE?0.71 (0.63–0.80)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 6 / 19.9Missense obs/exp: 189 / 266.3Syn Z: 0.66

This gene — mechanism propensity

0.78top 25%

GOF

0.77top 25%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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

57 submitted variants in ClinVar

ClinVar

Classification Summary

VUS47

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	47	47
Likely Benign	0	0
Benign	0	0
Total	47	47

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

View in ClinVar →

68 pathogenic / likely-pathogenic (of 80) ClinVar copy-number / structural variants overlap SH3BP5L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →