Is GEN1 p.Pro127= (c.381C>T) pathogenic?

GEN1 p.Pro127= (c.381C>T) is classified Likely benign in GEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). Absent from gnomAD v4.1.

How common is GEN1 p.Pro127= (c.381C>T) in the general population?

GEN1 p.Pro127= (c.381C>T) is absent from gnomAD v4.1 (gnomAD).

GEN1 p.Pro127=

c.381C>T · rs1288646494 · VCV2973928

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -1.3	GERP 0.14
Overall
CADD	9.312	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GEN1
Protein: p.Pro127=
Coding: c.381C>T
MANE Select: NM_001130009
dbSNP: rs1288646494
Type: single nucleotide variant
Location: chr2:17764929 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 127: the 'xpg-i domain' region

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

Similar variants

GEN1 p.Pro127Arg Uncertain significance ★ ⚠ same residue
GEN1 p.Pro127Leu Uncertain significance ★ same residue
GEN1 p.Pro127Ser 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

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-pro127 (accessed [today's date]).

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