Is GEN1 p.Pro267Ser (c.799C>T) pathogenic?

GEN1 p.Pro267Ser (c.799C>T) is classified Uncertain significance in GEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.6284); No allele count reported in gnomAD v4.1 (AN 1,577,120).

How common is GEN1 p.Pro267Ser (c.799C>T) in the general population?

GEN1 p.Pro267Ser (c.799C>T) is no allele count reported in gnomAD v4.1 (AN 1,577,120) (gnomAD).

What do computational predictors say about GEN1 p.Pro267Ser (c.799C>T)?

AlphaMissense predicts likely pathogenic (score 0.6284) — an in-silico prediction, not a clinical call.

GEN1 p.Pro267Ser

c.799C>T · VCV4263082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6284 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,577,120)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6284	likely pathogenic
REVEL	0.095	moderately benign-leaning
SaProt	LLR -11.98	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	23.2	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

No allele count reported in gnomAD v4.1 (AN 1,577,120). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GEN1
Protein: p.Pro267Ser
Coding: c.799C>T
MANE Select: NM_001130009
Type: single nucleotide variant
Location: chr2:17771284 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 267: the '5'-3' exonuclease domain' region

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

Similar variants

GEN1 p.Pro267Gln 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
GEN1 p.Ala448Thr 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-pro267ser (accessed [today's date]).

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