SH3GLB2

Chr 9

SH3 domain containing GRB2 like, endophilin B2

Also known as: PP6569, PP9455, RRIG1

NCBI Gene: 56904 ENSG00000148341 UniProt: Q9NR46

Enables identical protein binding activity. Predicted to be involved in membrane organization and postsynaptic neurotransmitter receptor internalization. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

1.4

Missense Z

0.74

LOEUF

Clinical Summary— SH3GLB2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

31 Pathogenic / Likely Pathogenic· 56 VUS of 89 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.74LOEUF

pLI 0.001

Z-score 2.40

OE 0.41 (0.24–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.38Z-score

OE missense 0.74 (0.65–0.84)

159 obs / 216.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.41 (0.24–0.74)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.65–0.84)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.14

0≤1.21.6

LoF obs/exp: 8 / 19.4Missense obs/exp: 159 / 216.3Syn Z: -1.06

0.74top 25%

GOF

0.71top 25%

LOF

0.2872th %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.