Is RAB3GAP2 p.Phe222Ser (c.665T>C) pathogenic?

RAB3GAP2 p.Phe222Ser (c.665T>C) is classified Uncertain significance in RAB3GAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.9564); Very rare (popmax 0.000255%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RAB3GAP2 p.Phe222Ser (c.665T>C)?

RAB3GAP2 p.Phe222Ser (c.665T>C) is associated with Inborn genetic diseases (ClinVar).

How common is RAB3GAP2 p.Phe222Ser (c.665T>C) in the general population?

RAB3GAP2 p.Phe222Ser (c.665T>C) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Phe222Ser (c.665T>C)?

AlphaMissense predicts likely pathogenic (score 0.9564) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Phe222Ser

c.665T>C · rs1310574245 · VCV2486993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9564	likely pathogenic · top 7% in RAB3GAP2
REVEL	0.47	indeterminate
SaProt	LLR -2.14	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 18 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	27.1	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 0.000255% European (non-Finnish) · 3/1,178,254 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,878 alleles · very rare exomes 2/1,459,660 · genomes 1/152,218 · 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.Phe222Ser
Coding: c.665T>C
MANE Select: NM_012414
dbSNP: rs1310574245
Type: single nucleotide variant
Location: chr1:220205954 (GRCh38)
Gene constraint: LOEUF 0.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 1 PDB
Residue 222: an α-helix

Full RAB3GAP2 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

Similar variants

RAB3GAP2 p.Arg1032Cys Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Arg35Trp Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Arg415Lys Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Asn1188Thr Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Asn697Ser Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Asn960Asp Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Asp1114Asn Uncertain significance ★★ ⚠ same condition
RAB3GAP2 p.Glu127Lys 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-phe222ser (accessed [today's date]).

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