Is WRN p.Ser683Pro (c.2047T>C) pathogenic?

WRN p.Ser683Pro (c.2047T>C) is classified Likely pathogenic in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: ambiguous (0.4351); Very rare (popmax 0.00446%, eas); Associated with ovarian cancer.

What condition is associated with WRN p.Ser683Pro (c.2047T>C)?

WRN p.Ser683Pro (c.2047T>C) is associated with ovarian cancer (ClinVar).

How common is WRN p.Ser683Pro (c.2047T>C) in the general population?

WRN p.Ser683Pro (c.2047T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about WRN p.Ser683Pro (c.2047T>C)?

AlphaMissense predicts ambiguous (score 0.4351) — an in-silico prediction, not a clinical call.

WRN p.Ser683Pro

c.2047T>C · rs1177166077 · VCV2445328

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4351 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.4351	ambiguous
REVEL	0.223	benign-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 88 kb · p 0.8 · regional, not allelic
Overall
CADD	22.4	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 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,008 alleles · very rare exomes 0/1,461,830 · genomes 2/152,178 · joint denominator

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.Ser683Pro
Coding: c.2047T>C
MANE Select: NM_000553
dbSNP: rs1177166077
Type: single nucleotide variant
Location: chr8:31100914 (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 683: an α-helix; the helicase atp-binding domain

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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WRN p.Ser683= Likely benign ★ same residue
WRN p.Ala1260Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Arg993His Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Asn277Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Asp1368Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Asp58Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Gly1298Val Conflicting classifications of pathogenicity ★ ⚠ same condition
WRN p.Ile710Val Conflicting classifications of pathogenicity ★ ⚠ 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-ser683pro (accessed [today's date]).

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