Is RAB3GAP1 p.Pro499Ser (c.1495C>T) pathogenic?

RAB3GAP1 p.Pro499Ser (c.1495C>T) is classified Uncertain significance in RAB3GAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-11). AlphaMissense: likely benign (0.1394); Very rare (popmax 0.00223%, eas).

How common is RAB3GAP1 p.Pro499Ser (c.1495C>T) in the general population?

RAB3GAP1 p.Pro499Ser (c.1495C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RAB3GAP1 p.Pro499Ser (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.1394) — an in-silico prediction, not a clinical call.

RAB3GAP1 p.Pro499Ser

c.1495C>T · rs1356056397 · VCV1309129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1394	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 29 kb · p 5.7e-08 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,834 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,604 alleles · very rare exomes 7/1,461,410 · genomes 0/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,834
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000424%	235,933

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.Pro499Ser
Coding: c.1495C>T
MANE Select: NM_012233
dbSNP: rs1356056397
Type: single nucleotide variant
Location: chr2:135134029 (GRCh38)
Gene constraint: LOEUF 0.798 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.46 · 1 PDB

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

Similar variants

RAB3GAP1 c.18+1G>C Likely pathogenic ★★ same type
RAB3GAP1 c.2607-1G>C Pathogenic ★★ same type
RAB3GAP1 c.748+1G>A Pathogenic ★★ same type
RAB3GAP1 c.899+1G>A Pathogenic ★★ same type
RAB3GAP1 p.Arg174Ter Pathogenic/Likely pathogenic ★★ same type
RAB3GAP1 p.Arg187Ter Pathogenic ★★ same type
RAB3GAP1 p.Arg231Ter Pathogenic ★★ same type
RAB3GAP1 p.Arg337Ter Pathogenic/Likely pathogenic ★★ same type

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-pro499ser (accessed [today's date]).

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