Is WRN p.Ser596= (c.1788T>C) pathogenic?

WRN p.Ser596= (c.1788T>C) is classified Benign/Likely benign in WRN (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.71%, afr); Associated with Wiskott-Aldrich syndrome.

What condition is associated with WRN p.Ser596= (c.1788T>C)?

WRN p.Ser596= (c.1788T>C) is associated with Wiskott-Aldrich syndrome, Werner syndrome (ClinVar).

How common is WRN p.Ser596= (c.1788T>C) in the general population?

WRN p.Ser596= (c.1788T>C) is low-frequency (popmax 1.71%, afr) (gnomAD).

How is Wiskott-Aldrich syndrome inherited?

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

WRN p.Ser596=

c.1788T>C · rs13438803 · VCV238130

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.71%, afr)

Conditions

Wiskott-Aldrich 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 -1.3	GERP -4.2
Overall
CADD	3.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.71% African / African-American · 1,279/74,984 alleles

Filtering AF 1.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.6%

Overall 0.085% 1,371/1,613,032 alleles · low-frequency exomes 657/1,460,834 · genomes 714/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.71%	59
Middle Eastern	0.0826%	1,211
Remaining individualsnot grpmax-eligible	0.072%	1,388
Admixed American	0.06%	1,666
European (non-Finnish)	0.000509%	196,545

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.Ser596=
Coding: c.1788T>C
MANE Select: NM_000553
dbSNP: rs13438803
Type: single nucleotide variant
Location: chr8:31090901 (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 596: the helicase atp-binding domain

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

Disease context

Wiskott-Aldrich syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Werner syndrome

For Wiskott-Aldrich syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

WRN p.Ser596Phe Uncertain significance ★ ⚠ same residue
WRN p.Ser596Pro 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-ser596 (accessed [today's date]).

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