Is WDR35 p.Arg459Pro (c.1376G>C) pathogenic?

WDR35 p.Arg459Pro (c.1376G>C) is classified Uncertain significance in WDR35 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-24). AlphaMissense: ambiguous (0.3911); Ultra-rare (popmax 0.0164%, mid).

How common is WDR35 p.Arg459Pro (c.1376G>C) in the general population?

WDR35 p.Arg459Pro (c.1376G>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about WDR35 p.Arg459Pro (c.1376G>C)?

AlphaMissense predicts ambiguous (score 0.3911) — an in-silico prediction, not a clinical call.

WDR35 p.Arg459Pro

c.1376G>C · VCV3600785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3911	ambiguous
REVEL	0.663	pathogenic-leaning
SaProt	LLR -8.30	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 76 kb · p 0.00014 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R470P vs ClinVar R459P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Overall 0.000124% 2/1,613,868 alleles · ultra-rare exomes 1/1,461,810 · genomes 1/152,058 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00134%	74,860

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: WDR35
Protein: p.Arg459Pro
Coding: c.1376G>C
MANE Select: NM_020779
Type: single nucleotide variant
Location: chr2:19953858 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 4 PDB

Full WDR35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WDR35 p.Arg459Gln Uncertain significance ★★ ⚠ same residue
WDR35 p.Arg459Trp Uncertain significance ★ ⚠ same residue
WDR35 c.1255+1G>A Pathogenic/Likely pathogenic ★★ same type
WDR35 c.2415-2A>G Likely pathogenic ★★ same type
WDR35 p.Arg332Ter Pathogenic ★★ same type
WDR35 p.Arg461Ter Pathogenic ★★ same type
WDR35 p.Arg564Ter Pathogenic/Likely pathogenic ★★ same type
WDR35 p.Arg582Ter Pathogenic/Likely pathogenic ★★ same type

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/wdr35-p-arg459pro (accessed [today's date]).

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