Is WNT4 p.Arg258= (c.774C>T) pathogenic?

WNT4 p.Arg258= (c.774C>T) is classified Uncertain significance in WNT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). Very rare (popmax 0.00833%, amr); Associated with mullerian aplasia and hyperandrogenism.

What condition is associated with WNT4 p.Arg258= (c.774C>T)?

WNT4 p.Arg258= (c.774C>T) is associated with mullerian aplasia and hyperandrogenism, SERKAL syndrome (ClinVar).

How common is WNT4 p.Arg258= (c.774C>T) in the general population?

WNT4 p.Arg258= (c.774C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

WNT4 p.Arg258=

c.774C>T · VCV3580610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

mullerian aplasia and hyperandrogenism

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 0.033	GERP -4.7, phastCons 0.53
Overall
CADD	3.561	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,018 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000372% 6/1,614,134 alleles · very rare exomes 5/1,461,848 · genomes 1/152,286 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: WNT4
Protein: p.Arg258=
Coding: c.774C>T
MANE Select: NM_030761
Type: single nucleotide variant
Location: chr1:22120332 (GRCh38)
Gene constraint: LOEUF 0.694 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 91.41

Full WNT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mullerian aplasia and hyperandrogenism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: SERKAL syndrome

Similar variants

WNT4 p.Arg258Cys Uncertain significance ★ ⚠ same residue
WNT4 p.Arg258His Uncertain significance ★ ⚠ same residue
WNT4 p.Ala114Ser Uncertain significance ★★ ⚠ same condition
WNT4 p.Ala223Thr Uncertain significance ★★ ⚠ same condition
WNT4 p.Arg126Gln Uncertain significance ★★ ⚠ same condition
WNT4 p.Arg126Trp Uncertain significance ★★ ⚠ same condition
WNT4 p.Arg247Cys Uncertain significance ★★ same condition
WNT4 p.Arg285His Uncertain significance ★★ ⚠ 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/wnt4-p-arg258 (accessed [today's date]).

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