Is WRN p.Ser600Pro (c.1798T>C) pathogenic?

WRN p.Ser600Pro (c.1798T>C) is classified Uncertain significance in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely pathogenic (0.7538); Very rare (popmax 8.48e-05%, nfe); Associated with Werner syndrome.

What condition is associated with WRN p.Ser600Pro (c.1798T>C)?

WRN p.Ser600Pro (c.1798T>C) is associated with Werner syndrome (ClinVar).

How common is WRN p.Ser600Pro (c.1798T>C) in the general population?

WRN p.Ser600Pro (c.1798T>C) is very rare (popmax 8.48e-05%, nfe) (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.Ser600Pro (c.1798T>C)?

AlphaMissense predicts likely pathogenic (score 0.7538) — an in-silico prediction, not a clinical call.

WRN p.Ser600Pro

c.1798T>C · rs1060500057 · VCV403980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Werner syndrome

Computational evidence

Protein change
AlphaMissense	0.7538	likely pathogenic
REVEL	0.409	indeterminate
SaProt	LLR -11.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.76, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 88 kb · p 0.8 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,268 alleles

Overall 6.2e-05% 1/1,613,060 alleles · very rare exomes 1/1,460,832 · genomes 0/152,228 · 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.Ser600Pro
Coding: c.1798T>C
MANE Select: NM_000553
dbSNP: rs1060500057
Type: single nucleotide variant
Location: chr8:31090911 (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 600: an α-helix; the helicase atp-binding domain

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 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
WRN c.2089-3024A>G Pathogenic/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-ser600pro (accessed [today's date]).

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