SGSM3

Chr 22AR

small G protein signaling modulator 3

Also known as: CIP85, MAP, MRT84, RABGAP5, RUSC3, RUTBC3, RabGAP-5, rabGAPLP

NCBI Gene: 27352 ENSG00000100359 UniProt: Q96HU1 OMIM: 610440

The SGSM3 protein functions as a GTPase-activating protein that accelerates GTP hydrolysis by Rab5, thereby controlling trafficking through the early endocytic pathway. Mutations in SGSM3 cause neurodevelopmental disorders with intellectual disability, typically following an autosomal recessive inheritance pattern. The gene shows minimal constraint against loss-of-function variants, which is consistent with recessive disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including Rap protein signal transduction; positive regulation of GTPase activity; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 84MIM #620401

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Intellectual developmental disorder, autosomal recessive 84; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.90

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 2.09

OE 0.66 (0.50–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.16Z-score

OE missense 0.98 (0.91–1.06)

475 obs / 485.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.50–0.90)

0≤0.351.4

Missense OE?0.98 (0.91–1.06)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 30 / 45.1Missense obs/exp: 475 / 485.0Syn Z: -1.72

Background carrier burden — how many people carry a rare variant somewhere in SGSM3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

1,132 rare PASS variants

Rare truncating (LoF)

1 in 690

218 rare PASS variants

Rare synonymous (reference)

1 in 44

541 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SGSM3. 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 51	1 in 840
South Asian	~43k	1 in 39	1 in 830
Remaining (unassigned)	~30k	1 in 41	1 in 390
European (Finnish)	~27k	1 in 140	1 in 2,900
Admixed American	~22k	1 in 47	1 in 960
African / African American	~21k	1 in 53	1 in 980
East Asian	~20k	1 in 39	1 in 680
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 42	≈ 1 in 1,400

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): 20 of 21 coding exons well covered in gnomAD exomes; exon 7 marginal. Genomes: all 21.? see exons ↓