Is WRN p.Val641Ala (c.1922T>C) pathogenic?

WRN p.Val641Ala (c.1922T>C) is classified Uncertain significance in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely benign (0.3284); Absent from gnomAD v4.1; Associated with Werner syndrome.

What condition is associated with WRN p.Val641Ala (c.1922T>C)?

WRN p.Val641Ala (c.1922T>C) is associated with Werner syndrome (ClinVar).

How common is WRN p.Val641Ala (c.1922T>C) in the general population?

WRN p.Val641Ala (c.1922T>C) is absent from gnomAD v4.1 (gnomAD).

How is Werner syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about WRN p.Val641Ala (c.1922T>C)?

AlphaMissense predicts likely benign (score 0.3284) — an in-silico prediction, not a clinical call.

WRN p.Val641Ala

c.1922T>C · rs1060500069 · VCV2872513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3284 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.3284	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -4.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 88 kb · p 0.8 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: WRN
Protein: p.Val641Ala
Coding: c.1922T>C
MANE Select: NM_000553
dbSNP: rs1060500069
Type: single nucleotide variant
Location: chr8:31096791 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.75 · 51 PDB
Residue 641: a β-strand; the helicase atp-binding domain

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

Disease context

Werner syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Werner syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

WRN p.Val641Glu Uncertain significance ★ ⚠ same residue
WRN p.Val641Ile Uncertain significance ★ ⚠ same residue
WRN p.Val641Leu Uncertain significance ★ ⚠ same residue
WRN p.Val641= Likely benign ★ same residue
WRN c.1351-1G>A Likely pathogenic ★★ same condition
WRN c.1351-2A>G Likely pathogenic ★★ same condition
WRN c.1432-2A>T Likely pathogenic ★★ same condition
WRN c.1652+1G>A Likely pathogenic ★★ 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/wrn-p-val641ala (accessed [today's date]).

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