Is RAB3GAP2 p.Leu258= (c.774A>G) pathogenic?

RAB3GAP2 p.Leu258= (c.774A>G) is classified Conflicting classifications of pathogenicity in RAB3GAP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-16). Rare (popmax 0.109%, sas); Associated with Martsolf syndrome.

What condition is associated with RAB3GAP2 p.Leu258= (c.774A>G)?

RAB3GAP2 p.Leu258= (c.774A>G) is associated with Martsolf syndrome, Warburg micro syndrome 2 (ClinVar).

How common is RAB3GAP2 p.Leu258= (c.774A>G) in the general population?

RAB3GAP2 p.Leu258= (c.774A>G) is rare (popmax 0.109%, sas) (gnomAD).

RAB3GAP2 p.Leu258=

c.774A>G · rs576411922 · VCV130073

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.109%, sas)

Conditions

Martsolf syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.169	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -3.6
Overall
CADD	3.765	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.109% South Asian · 99/91,078 alleles

Filtering AF 0.0914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0849%

Overall 0.00694% 112/1,613,972 alleles · rare exomes 101/1,461,632 · genomes 11/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.109%	920
Remaining individualsnot grpmax-eligible	0.0208%	4,807

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.Leu258=
Coding: c.774A>G
MANE Select: NM_012414
dbSNP: rs576411922
Type: single nucleotide variant
Location: chr1:220202313 (GRCh38)
Gene constraint: LOEUF 0.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 1 PDB
Residue 258: a β-strand

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-leu258 (accessed [today's date]).

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