Is RAB3GAP2 p.Pro1253Ser (c.3757C>T) pathogenic?

RAB3GAP2 p.Pro1253Ser (c.3757C>T) is classified Conflicting classifications of pathogenicity in RAB3GAP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1326); Rare (popmax 0.323%, sas); Associated with Martsolf syndrome.

What condition is associated with RAB3GAP2 p.Pro1253Ser (c.3757C>T)?

RAB3GAP2 p.Pro1253Ser (c.3757C>T) is associated with Martsolf syndrome, Warburg micro syndrome 2 (ClinVar).

How common is RAB3GAP2 p.Pro1253Ser (c.3757C>T) in the general population?

RAB3GAP2 p.Pro1253Ser (c.3757C>T) is rare (popmax 0.323%, sas) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Pro1253Ser (c.3757C>T)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Pro1253Ser

c.3757C>T · rs564016323 · VCV676620

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.323%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Martsolf syndrome

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 16 kb · p 0.0014 · regional, not allelic
Overall
CADD	21.7	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 0.323% South Asian · 294/91,084 alleles

Filtering AF 0.292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.0188% 303/1,614,112 alleles · rare exomes 286/1,461,812 · genomes 17/152,300 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.323%	310
Remaining individualsnot grpmax-eligible	0.008%	12,500
East Asian	0.00223%	44,880
Admixed American	0.00167%	60,020
African / African-American	0.00133%	75,042
European (non-Finnish)	8.47e-05%	1,179,974

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.Pro1253Ser
Coding: c.3757C>T
MANE Select: NM_012414
dbSNP: rs564016323
Type: single nucleotide variant
Location: chr1:220153295 (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

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

Also linked: Warburg micro syndrome 2

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-pro1253ser (accessed [today's date]).

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