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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.60

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in SH3BP5L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

504 rare PASS variants

Rare truncating (LoF)

1 in 7,400

45 rare PASS variants

Rare synonymous (reference)

1 in 140

247 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH3BP5L. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 7,200
South Asian	~43k	1 in 190	1 in 8,600
Remaining (unassigned)	~30k	1 in 150	1 in 4,300
European (Finnish)	~27k	1 in 220	≈ 1 in 13,000
Admixed American	~22k	1 in 170	1 in 3,800
African / African American	~21k	1 in 200	≈ 1 in 17,000
East Asian	~20k	1 in 310	none seen
Ashkenazi Jewish	~13k	1 in 350	none seen
Middle Eastern	~2,884	1 in 150	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓