Is WRN p.Phe618= (c.1854C>T) pathogenic?

WRN p.Phe618= (c.1854C>T) is classified Likely benign in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). Very rare (popmax 0.0011%, sas); Associated with Werner syndrome.

What condition is associated with WRN p.Phe618= (c.1854C>T)?

WRN p.Phe618= (c.1854C>T) is associated with Werner syndrome (ClinVar).

How common is WRN p.Phe618= (c.1854C>T) in the general population?

WRN p.Phe618= (c.1854C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Werner syndrome inherited?

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

WRN p.Phe618=

c.1854C>T · rs2130178599 · VCV1120977

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Werner syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.35	GERP -3.6, phastCons 0.99
Overall
CADD	7.236	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,066 alleles

Overall 0.000124% 2/1,613,194 alleles · very rare exomes 2/1,460,964 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	8.48e-05%	1,179,389

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.Phe618=
Coding: c.1854C>T
MANE Select: NM_000553
dbSNP: rs2130178599
Type: single nucleotide variant
Location: chr8:31091854 (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 618: a β-strand; 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 p.Phe618Cys Uncertain significance ★ ⚠ same residue
WRN p.Phe618Ser 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-phe618 (accessed [today's date]).

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