Is WRN p.Val281Phe (c.841G>T) pathogenic?

WRN p.Val281Phe (c.841G>T) is classified Uncertain significance in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.1735); Very rare (popmax 0.00447%, eas); Associated with Werner syndrome.

What condition is associated with WRN p.Val281Phe (c.841G>T)?

WRN p.Val281Phe (c.841G>T) is associated with Werner syndrome (ClinVar).

How common is WRN p.Val281Phe (c.841G>T) in the general population?

WRN p.Val281Phe (c.841G>T) is very rare (popmax 0.00447%, eas) (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.Val281Phe (c.841G>T)?

AlphaMissense predicts likely benign (score 0.1735) — an in-silico prediction, not a clinical call.

WRN p.Val281Phe

c.841G>T · rs1060500055 · VCV403978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.1735	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -7.44	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 0.11	GERP -1.9, phastCons 0.071
Regional constraint	o/e 0.99	unconstrained · MANE · 25 kb · p 0.86 · regional, not allelic
Overall
CADD	17.08	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

Grpmax group 0.00447% East Asian · 2/44,728 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000313% 5/1,597,688 alleles · very rare exomes 5/1,445,864 · genomes 0/151,824 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,364
Remaining individualsnot grpmax-eligible	0.00162%	61,718
South Asian	0.00114%	87,768
European (non-Finnish)	8.52e-05%	1,173,698

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: WRN
Protein: p.Val281Phe
Coding: c.841G>T
MANE Select: NM_000553
dbSNP: rs1060500055
Type: single nucleotide variant
Location: chr8:31080868 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.75 · 51 PDB

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.Val281Ile Uncertain significance ★ ⚠ 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
WRN c.1720+5G>A Likely pathogenic ★★ same condition
WRN c.1721-1G>A Likely pathogenic ★★ same condition
WRN c.1829+5G>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-val281phe (accessed [today's date]).

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