Is WDR45 p.Lys89Asn (c.267G>C) pathogenic?

WDR45 p.Lys89Asn (c.267G>C) is classified Uncertain significance in WDR45 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-15). AlphaMissense: ambiguous (0.355); Absent from gnomAD v4.1; Associated with neurodegeneration with brain iron accumulation 5.

What condition is associated with WDR45 p.Lys89Asn (c.267G>C)?

WDR45 p.Lys89Asn (c.267G>C) is associated with neurodegeneration with brain iron accumulation 5 (ClinVar).

How common is WDR45 p.Lys89Asn (c.267G>C) in the general population?

WDR45 p.Lys89Asn (c.267G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about WDR45 p.Lys89Asn (c.267G>C)?

AlphaMissense predicts ambiguous (score 0.355) — an in-silico prediction, not a clinical call.

WDR45 p.Lys89Asn

Q: How is Beta-propeller protein-associated neurodegeneration inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.267G>C · rs1557084325 · VCV473120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.355 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neurodegeneration with brain iron accumulation 5

Computational evidence

Protein change
AlphaMissense	0.355	ambiguous
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.72, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 2,402 bp · p 8.3e-07 · regional, not allelic
Overall
CADD	19.99	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: WDR45
Protein: p.Lys89Asn
Coding: c.267G>C
MANE Select: NM_001029896
dbSNP: rs1557084325
Type: single nucleotide variant
Location: chrX:49076719 (GRCh38)
Structure: AlphaFold pLDDT 90.66 · 3 PDB
Residue 89: a UniProt-annotated variant site (in nbia5)

Full WDR45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodegeneration with brain iron accumulation 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Beta-propeller protein-associated neurodegeneration (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood

Similar variants

WDR45 c.342-2A>G Pathogenic/Likely pathogenic ★★ same condition
WDR45 c.342-3C>G Pathogenic/Likely pathogenic ★★ same condition
WDR45 c.437-1G>A Pathogenic/Likely pathogenic ★★ same condition
WDR45 c.437-2A>G Pathogenic ★★ same condition
WDR45 c.516+1G>A Pathogenic ★★ same condition
WDR45 c.726-1G>A Pathogenic ★★ same condition
WDR45 c.726-2A>G Pathogenic ★★ same condition
WDR45 c.827+1G>A 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/wdr45-p-lys89asn (accessed [today's date]).

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