Is WRN p.Phe46Ser (c.137T>C) pathogenic?

WRN p.Phe46Ser (c.137T>C) is classified Uncertain significance in WRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-01). AlphaMissense: ambiguous (0.4212); Ultra-rare (popmax 0.065%, amr); Associated with Werner syndrome.

What condition is associated with WRN p.Phe46Ser (c.137T>C)?

WRN p.Phe46Ser (c.137T>C) is associated with Werner syndrome (ClinVar).

How common is WRN p.Phe46Ser (c.137T>C) in the general population?

WRN p.Phe46Ser (c.137T>C) is ultra-rare (popmax 0.065%, amr) (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.Phe46Ser (c.137T>C)?

AlphaMissense predicts ambiguous (score 0.4212) — an in-silico prediction, not a clinical call.

WRN p.Phe46Ser

c.137T>C · rs772246871 · VCV569940

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.065%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.4212	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.53, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 25 kb · p 0.86 · regional, not allelic
Overall
CADD	23.0	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 0.065% Admixed American · 39/60,012 alleles

Filtering AF 0.0488% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0432%

Overall 0.00248% 40/1,613,764 alleles · ultra-rare exomes 39/1,461,574 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.065%	1,539
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Phe46Ser
Coding: c.137T>C
MANE Select: NM_000553
dbSNP: rs772246871
Type: single nucleotide variant
Location: chr8:31059193 (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 46: the 'interaction with wrnip1' region

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.Phe46Leu Uncertain significance ★ ⚠ same residue
WRN p.Phe46del 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

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-phe46ser (accessed [today's date]).

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