Is WRN p.Ser115Phe (c.344C>T) pathogenic?

WRN p.Ser115Phe (c.344C>T) is classified Uncertain significance in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.4551); Ultra-rare (popmax 0.0164%, mid); Associated with Werner syndrome.

What condition is associated with WRN p.Ser115Phe (c.344C>T)?

WRN p.Ser115Phe (c.344C>T) is associated with Werner syndrome (ClinVar).

How common is WRN p.Ser115Phe (c.344C>T) in the general population?

WRN p.Ser115Phe (c.344C>T) is ultra-rare (popmax 0.0164%, mid) (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.Ser115Phe (c.344C>T)?

AlphaMissense predicts ambiguous (score 0.4551) — an in-silico prediction, not a clinical call.

WRN p.Ser115Phe

c.344C>T · rs1362437279 · VCV1001622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4551 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.4551	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -10.23	damaging
Splicing
SpliceAI	Δ0.22	donor loss · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 25 kb · p 0.86 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,962 alleles · ultra-rare exomes 6/1,461,794 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000424%	236,000

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.Ser115Phe
Coding: c.344C>T
MANE Select: NM_000553
dbSNP: rs1362437279
Type: single nucleotide variant
Location: chr8:31064423 (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 115: the 3'-5' exonuclease domain; the 'interaction with wrnip1' region; an α-helix

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.Ser115= 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
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-ser115phe (accessed [today's date]).

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