Is RAB3GAP2 p.Ser654Pro (c.1960T>C) pathogenic?

RAB3GAP2 p.Ser654Pro (c.1960T>C) is classified Uncertain significance in RAB3GAP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2973); Ultra-rare (popmax 0.063%, afr); Associated with Warburg micro syndrome 2.

What condition is associated with RAB3GAP2 p.Ser654Pro (c.1960T>C)?

RAB3GAP2 p.Ser654Pro (c.1960T>C) is associated with Warburg micro syndrome 2, Martsolf syndrome, Martsolf syndrome 1 (ClinVar).

How common is RAB3GAP2 p.Ser654Pro (c.1960T>C) in the general population?

RAB3GAP2 p.Ser654Pro (c.1960T>C) is ultra-rare (popmax 0.063%, afr) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Ser654Pro (c.1960T>C)?

AlphaMissense predicts likely benign (score 0.2973) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Ser654Pro

c.1960T>C · rs147587414 · VCV295655

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.063%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Warburg micro syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2973	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -12.31	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.67, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	17.34	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 0.063% African / African-American · 47/74,634 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0436%

Overall 0.00363% 58/1,596,442 alleles · ultra-rare exomes 24/1,444,168 · genomes 34/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.063%	1,588
Remaining individualsnot grpmax-eligible	0.0113%	8,831
Admixed American	0.00668%	14,974

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.Ser654Pro
Coding: c.1960T>C
MANE Select: NM_012414
dbSNP: rs147587414
Type: single nucleotide variant
Location: chr1:220184074 (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

Disease context

Warburg micro syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Martsolf syndrome Martsolf syndrome 1

Similar variants

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
RAB3GAP2 p.Ala684Glu 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-ser654pro (accessed [today's date]).

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