Is GEN1 p.Val377= (c.1131A>G) pathogenic?

GEN1 p.Val377= (c.1131A>G) is classified Likely benign in GEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-06). Very rare (popmax 0.00334%, amr).

How common is GEN1 p.Val377= (c.1131A>G) in the general population?

GEN1 p.Val377= (c.1131A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

GEN1 p.Val377=

c.1131A>G · VCV3716449

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -4.2, phastCons 1
Overall
CADD	4.563	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,838 alleles

Filtering AF 0.000619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000477%

Overall 0.000935% 15/1,603,728 alleles · very rare exomes 13/1,451,570 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,919
European (non-Finnish)	0.00111%	90,180

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: GEN1
Protein: p.Val377=
Coding: c.1131A>G
MANE Select: NM_001130009
Type: single nucleotide variant
Location: chr2:17774330 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 377: the '5'-3' exonuclease domain' region; an α-helix

Full GEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GEN1 p.Val377Ile Uncertain significance ★★ ⚠ same residue
GEN1 p.Val377Ala Uncertain significance ★ ⚠ same residue
GEN1 c.1264+1G>T Uncertain significance ★★ same type
GEN1 c.953+4A>G Uncertain significance ★★ same type
GEN1 p.Ala135Ser Uncertain significance ★★ ⚠ same type
GEN1 p.Ala197Thr Uncertain significance ★★ ⚠ same type
GEN1 p.Ala320Pro Uncertain significance ★★ ⚠ same type
GEN1 p.Ala447Val Uncertain significance ★★ ⚠ same type

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/gen1-p-val377 (accessed [today's date]).

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