Is RAB3GAP2 p.Leu764Phe (c.2290C>T) pathogenic?

RAB3GAP2 p.Leu764Phe (c.2290C>T) is classified Conflicting classifications of pathogenicity in RAB3GAP2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0645); Rare (popmax 0.189%, nfe); Associated with Warburg micro syndrome 2.

What condition is associated with RAB3GAP2 p.Leu764Phe (c.2290C>T)?

RAB3GAP2 p.Leu764Phe (c.2290C>T) is associated with Warburg micro syndrome 2, Martsolf syndrome (ClinVar).

How common is RAB3GAP2 p.Leu764Phe (c.2290C>T) in the general population?

RAB3GAP2 p.Leu764Phe (c.2290C>T) is rare (popmax 0.189%, nfe) (gnomAD).

What do computational predictors say about RAB3GAP2 p.Leu764Phe (c.2290C>T)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

RAB3GAP2 p.Leu764Phe

c.2290C>T · rs139337049 · VCV235683

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.189%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Warburg micro syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -4.32	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 4.5	GERP 0.008, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	16.97	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 0.189% European (non-Finnish) · 2,230/1,179,946 alleles

Filtering AF 0.182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.157% 2,534/1,613,938 alleles · rare exomes 2,386/1,461,762 · genomes 148/152,176 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.227%	440
Ashkenazi Jewishnot grpmax-eligible	0.199%	502
European (non-Finnish)grpmax	0.189%	529
Middle Eastern	0.099%	1,010
Admixed American	0.05%	2,000
South Asian	0.045%	2,221
African / African-American	0.0267%	3,751
Finnishnot grpmax-eligible	0.00938%	10,665

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu764Phe
Coding: c.2290C>T
MANE Select: NM_012414
dbSNP: rs139337049
Type: single nucleotide variant
Location: chr1:220182277 (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

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-leu764phe (accessed [today's date]).

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