Is GEN1 p.Pro351Ser (c.1051C>T) pathogenic?

GEN1 p.Pro351Ser (c.1051C>T) is classified Uncertain significance in GEN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.9489); Very rare (popmax 0.000515%, nfe).

How common is GEN1 p.Pro351Ser (c.1051C>T) in the general population?

GEN1 p.Pro351Ser (c.1051C>T) is very rare (popmax 0.000515%, nfe) (gnomAD).

What do computational predictors say about GEN1 p.Pro351Ser (c.1051C>T)?

AlphaMissense predicts likely pathogenic (score 0.9489) — an in-silico prediction, not a clinical call.

GEN1 p.Pro351Ser

c.1051C>T · VCV4671505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000515%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9489	likely pathogenic · top 4% in GEN1
REVEL	0.392	indeterminate
SaProt	LLR -13.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000515% European (non-Finnish) · 6/1,165,880 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000377% 6/1,593,250 alleles · very rare exomes 6/1,441,274 · genomes 0/151,976 · joint denominator

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.Pro351Ser
Coding: c.1051C>T
MANE Select: NM_001130009
Type: single nucleotide variant
Location: chr2:17773279 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 351: the '5'-3' exonuclease domain' region

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

Similar variants

GEN1 p.Pro351= Likely benign ★★ 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-pro351ser (accessed [today's date]).

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