Is WRN p.Ser462= (c.1386C>G) pathogenic?

WRN p.Ser462= (c.1386C>G) is classified Likely benign in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). Very rare (popmax 8.48e-05%, nfe); Associated with Werner syndrome.

What condition is associated with WRN p.Ser462= (c.1386C>G)?

WRN p.Ser462= (c.1386C>G) is associated with Werner syndrome (ClinVar).

How common is WRN p.Ser462= (c.1386C>G) in the general population?

WRN p.Ser462= (c.1386C>G) 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.

WRN p.Ser462=

c.1386C>G · rs2535919356 · VCV2714032

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

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

Conditions

Werner syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -2.8, phastCons 0.98
Overall
CADD	1.334	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,284 alleles

Overall 6.2e-05% 1/1,612,422 alleles · very rare exomes 1/1,460,828 · genomes 0/151,594 · 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.Ser462=
Coding: c.1386C>G
MANE Select: NM_000553
dbSNP: rs2535919356
Type: single nucleotide variant
Location: chr8:31085201 (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 462: the '2 x 27 aa tandem repeats of h-l-s-p-n-d-n-e-n-d-t-s-y-v-i-e-s-d-e-d-l-e-m-e-m-l-k' 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.Ser462Ala Uncertain significance ★ ⚠ same residue
WRN p.Ser462Pro Uncertain significance ★ ⚠ same residue
WRN p.Ser462Thr 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

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-ser462 (accessed [today's date]).

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