Is WDR45 p.Arg86= (c.256C>A) pathogenic?

WDR45 p.Arg86= (c.256C>A) is classified Likely benign in WDR45 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-27). Very rare (popmax 0.00246%, nfe); Associated with neurodegeneration with brain iron accumulation 5.

What condition is associated with WDR45 p.Arg86= (c.256C>A)?

WDR45 p.Arg86= (c.256C>A) is associated with neurodegeneration with brain iron accumulation 5 (ClinVar).

How common is WDR45 p.Arg86= (c.256C>A) in the general population?

WDR45 p.Arg86= (c.256C>A) is very rare (popmax 0.00246%, nfe) (gnomAD).

WDR45 p.Arg86=

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.256C>A · rs139837168 · VCV3022919

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

neurodegeneration with brain iron accumulation 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.41	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 0.74, phastCons 1
Overall
CADD	14.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 22/892,574 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.00182% 22/1,206,415 alleles · very rare exomes 22/1,092,671 · genomes 0/113,744 · joint denominator

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: WDR45
Protein: p.Arg86=
Coding: c.256C>A
MANE Select: NM_001029896
dbSNP: rs139837168
Type: single nucleotide variant
Location: chrX:49076730 (GRCh38)
Structure: AlphaFold pLDDT 90.66 · 3 PDB
Residue 86: 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 p.Arg86Gln Benign/Likely benign ★★ same residue
WDR45 p.Arg86Leu Uncertain significance ★ ⚠ same residue
WDR45 p.Arg86Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg86 (accessed [today's date]).

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