Is RAB3GAP2 p.Asp665Ala (c.1994A>C) pathogenic?

RAB3GAP2 p.Asp665Ala (c.1994A>C) is classified Uncertain significance in RAB3GAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-18). AlphaMissense: likely benign (0.0921); Very rare (popmax 0.00132%, nfe).

How common is RAB3GAP2 p.Asp665Ala (c.1994A>C) in the general population?

RAB3GAP2 p.Asp665Ala (c.1994A>C) is very rare (popmax 0.00132%, nfe) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Asp665Ala (c.1994A>C)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Asp665Ala

c.1994A>C · rs368311514 · VCV1311233

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00132%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP -0.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	19.91	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 0.00132% European (non-Finnish) · 15/1,137,404 alleles

Filtering AF 0.000792% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000628%

Overall 0.00096% 15/1,562,642 alleles · very rare exomes 14/1,410,480 · genomes 1/152,162 · joint denominator

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.Asp665Ala
Coding: c.1994A>C
MANE Select: NM_012414
dbSNP: rs368311514
Type: single nucleotide variant
Location: chr1:220184040 (GRCh38)
Gene constraint: LOEUF 0.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 1 PDB

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

Similar variants

RAB3GAP2 p.Asp665= Likely benign ★ same residue
RAB3GAP2 c.713-2A>C Likely pathogenic ★★ same type
RAB3GAP2 p.Arg1213Ter Pathogenic ★★ same type
RAB3GAP2 p.Arg426Cys Pathogenic/Likely pathogenic ★★ same type
RAB3GAP2 c.1631+8G>T Uncertain significance ★★ same type
RAB3GAP2 c.*2171A>G Uncertain significance ★★ same type
RAB3GAP2 p.Ala16Thr Uncertain significance ★★ ⚠ same type
RAB3GAP2 p.Ala240Pro Uncertain significance ★★ ⚠ 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/rab3gap2-p-asp665ala (accessed [today's date]).

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