Is WRN p.Ser394= (c.1182G>A) pathogenic?

WRN p.Ser394= (c.1182G>A) is classified Likely benign in WRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0218%, nfe); Associated with Werner syndrome.

What condition is associated with WRN p.Ser394= (c.1182G>A)?

WRN p.Ser394= (c.1182G>A) is associated with Werner syndrome (ClinVar).

How common is WRN p.Ser394= (c.1182G>A) in the general population?

WRN p.Ser394= (c.1182G>A) is ultra-rare (popmax 0.0218%, nfe) (gnomAD).

How is Werner syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

WRN p.Ser394=

c.1182G>A · rs138565529 · VCV412706

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, 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 -7.2	GERP -3.5
Overall
CADD	1.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% European (non-Finnish) · 257/1,179,844 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0181% 292/1,613,790 alleles · ultra-rare exomes 277/1,461,516 · genomes 15/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0218%	4,591
Admixed American	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.016%	6,248
South Asian	0.0143%	7,004
African / African-American	0.00267%	37,498

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.Ser394=
Coding: c.1182G>A
MANE Select: NM_000553
dbSNP: rs138565529
Type: single nucleotide variant
Location: chr8:31081209 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.75 · 51 PDB

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.Ser394Trp Uncertain significance ★★ same residue
WRN p.Ser394Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser394 (accessed [today's date]).

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