SGSM2

Chr 17

small G protein signaling modulator 2

Also known as: RUTBC1

NCBI Gene: 9905 ENSG00000141258 UniProt: O43147

The encoded protein functions as a GTPase activator that inactivates RAB32, RAB33B, and RAB38, thereby regulating membrane trafficking and the transport of melanogenic enzymes to melanosomes in melanocytes. Mutations cause autosomal recessive oculocutaneous albinism, characterized by reduced pigmentation affecting the eyes and skin. This gene shows low constraint to loss-of-function variation.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a GTPase activator with activity towards RAB32 and RAB33B, which are regulators of membrane trafficking. The encoded protein inactivates RAB32 and can bind RAB9A-GTP, a protein required for RAB32 activation. [provided by RefSeq, Oct 2016]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— SGSM2

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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

192 VUS of 222 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 3.95

OE 0.43 (0.31–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.30Z-score

OE missense 0.97 (0.91–1.03)

649 obs / 670.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.31–0.60)

0≤0.351.4

Missense OE?0.97 (0.91–1.03)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 24 / 55.9Missense obs/exp: 649 / 670.8Syn Z: -1.49

This gene — mechanism propensity

0.6840th %ile

GOF

0.72top 25%

LOF

0.2872th %ile

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

GOFprediction above median

DNprediction 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

222 submitted variants in ClinVar

ClinVar

Classification Summary

VUS192

Likely Benign2

Benign5

192

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	192	0	192
Likely Benign	1	1	2
Benign	2	3	5
Total	195	4	199

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 76) ClinVar copy-number / structural variants overlap SGSM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →