Is RAB3GAP2 p.Pro366Leu (c.1097C>T) pathogenic?

RAB3GAP2 p.Pro366Leu (c.1097C>T) is classified Uncertain significance in RAB3GAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.1912); Very rare (popmax 0.00329%, sas); Associated with Martsolf syndrome.

What condition is associated with RAB3GAP2 p.Pro366Leu (c.1097C>T)?

RAB3GAP2 p.Pro366Leu (c.1097C>T) is associated with Martsolf syndrome, Warburg micro syndrome 2 (ClinVar).

How common is RAB3GAP2 p.Pro366Leu (c.1097C>T) in the general population?

RAB3GAP2 p.Pro366Leu (c.1097C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.1912) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Pro366Leu

c.1097C>T · rs988513386 · VCV1413228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Martsolf syndrome

Computational evidence

Protein change
AlphaMissense	0.1912	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 18 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	31.0	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00105% 17/1,613,946 alleles · very rare exomes 16/1,461,826 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
East Asian	0.00223%	44,878
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000932%	107,273

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_012414
dbSNP: rs988513386
Type: single nucleotide variant
Location: chr1:220195111 (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-pro366leu (accessed [today's date]).

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