Is RAB3GAP2 p.Arg166Cys (c.496C>T) pathogenic?

RAB3GAP2 p.Arg166Cys (c.496C>T) is classified Uncertain significance in RAB3GAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-20). AlphaMissense: likely benign (0.1747); Very rare (popmax 0.0033%, sas); Associated with Martsolf syndrome.

What condition is associated with RAB3GAP2 p.Arg166Cys (c.496C>T)?

RAB3GAP2 p.Arg166Cys (c.496C>T) is associated with Martsolf syndrome, Warburg micro syndrome 2 (ClinVar).

How common is RAB3GAP2 p.Arg166Cys (c.496C>T) in the general population?

RAB3GAP2 p.Arg166Cys (c.496C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1747) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Arg166Cys

c.496C>T · rs747770349 · VCV1975307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Martsolf syndrome

Computational evidence

Protein change
AlphaMissense	0.1747	likely benign
REVEL	0.666	pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 18 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% South Asian · 3/91,008 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00124% 20/1,613,160 alleles · very rare exomes 18/1,461,022 · genomes 2/152,138 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,336
Remaining individualsnot grpmax-eligible	0.0032%	31,225
African / African-American	0.00267%	37,422
Finnishnot grpmax-eligible	0.00156%	63,992
European (non-Finnish)	0.00102%	98,298

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RAB3GAP2
Protein: p.Arg166Cys
Coding: c.496C>T
MANE Select: NM_012414
dbSNP: rs747770349
Type: single nucleotide variant
Location: chr1:220210815 (GRCh38)
Gene constraint: LOEUF 0.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 1 PDB
Residue 166: a β-strand

Full RAB3GAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Martsolf syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Warburg micro syndrome 2

Similar variants

RAB3GAP2 p.Arg166His Uncertain significance ★ ⚠ same residue
RAB3GAP2 c.713-2A>C Likely pathogenic ★★ same condition
RAB3GAP2 p.Arg1213Ter Pathogenic ★★ same condition
RAB3GAP2 p.Arg426Cys Pathogenic/Likely pathogenic ★★ same condition
RAB3GAP2 c.*2171A>G Uncertain significance ★★ same condition
RAB3GAP2 p.Ala16Thr Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Ala240Pro Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Ala300Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rab3gap2-p-arg166cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown