Is WRN p.Phe64Ser (c.191T>C) pathogenic?

WRN p.Phe64Ser (c.191T>C) is classified Uncertain significance in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: ambiguous (0.4224); Very rare (popmax 0.00223%, eas); Associated with Werner syndrome.

What condition is associated with WRN p.Phe64Ser (c.191T>C)?

WRN p.Phe64Ser (c.191T>C) is associated with Werner syndrome (ClinVar).

How common is WRN p.Phe64Ser (c.191T>C) in the general population?

WRN p.Phe64Ser (c.191T>C) is very rare (popmax 0.00223%, 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.Phe64Ser (c.191T>C)?

AlphaMissense predicts ambiguous (score 0.4224) — an in-silico prediction, not a clinical call.

WRN p.Phe64Ser

c.191T>C · rs2130005674 · VCV1446754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.4224	ambiguous
REVEL	0.368	indeterminate
SaProt	LLR -3.80	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 25 kb · p 0.86 · regional, not allelic
Overall
CADD	23.1	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 0.00223% East Asian · 1/44,786 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,528 alleles · very rare exomes 3/1,461,186 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,786
European (non-Finnish)	0.00017%	589,793

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.Phe64Ser
Coding: c.191T>C
MANE Select: NM_000553
dbSNP: rs2130005674
Type: single nucleotide variant
Location: chr8:31059247 (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 64: 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.Phe64Leu 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-phe64ser (accessed [today's date]).

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