Is RAB3GAP1 p.Phe331Leu (c.991T>C) pathogenic?

RAB3GAP1 p.Phe331Leu (c.991T>C) is classified Uncertain significance in RAB3GAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.8627); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with RAB3GAP1 p.Phe331Leu (c.991T>C)?

RAB3GAP1 p.Phe331Leu (c.991T>C) is associated with Inborn genetic diseases, Warburg micro syndrome 1 (ClinVar).

How common is RAB3GAP1 p.Phe331Leu (c.991T>C) in the general population?

RAB3GAP1 p.Phe331Leu (c.991T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about RAB3GAP1 p.Phe331Leu (c.991T>C)?

AlphaMissense predicts likely pathogenic (score 0.8627) — an in-silico prediction, not a clinical call.

RAB3GAP1 p.Phe331Leu

c.991T>C · rs1352325000 · VCV3065165

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8627	likely pathogenic
REVEL	0.247	benign-leaning
SaProt	LLR -3.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 82 kb · p 0.34 · regional, not allelic
Overall
CADD	23.8	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00062% 10/1,612,244 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
European (non-Finnish)	0.000679%	147,377

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: RAB3GAP1
Protein: p.Phe331Leu
Coding: c.991T>C
MANE Select: NM_012233
dbSNP: rs1352325000
Type: single nucleotide variant
Location: chr2:135130012 (GRCh38)
Gene constraint: LOEUF 0.798 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.46 · 1 PDB
Residue 331: an α-helix

Full RAB3GAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Warburg micro syndrome 1

Similar variants

RAB3GAP1 c.2607-1G>C Pathogenic ★★ same condition
RAB3GAP1 c.748+1G>A Pathogenic ★★ same condition
RAB3GAP1 c.899+1G>A Pathogenic ★★ same condition
RAB3GAP1 p.Arg187Ter Pathogenic ★★ same condition
RAB3GAP1 p.Arg337Ter Pathogenic/Likely pathogenic ★★ same condition
RAB3GAP1 p.Arg347Ter Pathogenic ★★ same condition
RAB3GAP1 p.Arg392Ter Pathogenic ★★ same condition
RAB3GAP1 p.Gln246Ter Pathogenic ★★ 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/rab3gap1-p-phe331leu (accessed [today's date]).

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