Is WDR35 p.Arg353Pro (c.1058G>C) pathogenic?

WDR35 p.Arg353Pro (c.1058G>C) is classified Benign/Likely benign in WDR35 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.8852); Rare (popmax 0.988%, eas); Associated with short-rib thoracic dysplasia 7 with or without polydactyly.

How common is WDR35 p.Arg353Pro (c.1058G>C) in the general population?

WDR35 p.Arg353Pro (c.1058G>C) is rare (popmax 0.988%, eas) (gnomAD).

What do computational predictors say about WDR35 p.Arg353Pro (c.1058G>C)?

AlphaMissense predicts likely pathogenic (score 0.8852) — an in-silico prediction, not a clinical call.

WDR35 p.Arg353Pro

Q: What condition is associated with WDR35 p.Arg353Pro (c.1058G>C)?

WDR35 p.Arg353Pro (c.1058G>C) is associated with short-rib thoracic dysplasia 7 with or without polydactyly, cranioectodermal dysplasia 2 (ClinVar).

c.1058G>C · rs76623454 · VCV333397

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8852 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.988%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

short-rib thoracic dysplasia 7 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.8852	likely pathogenic · top 10% in WDR35
REVEL	0.491	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 76 kb · p 0.00014 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.988% East Asian · 443/44,836 alleles

Filtering AF 0.912% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.882%

Overall 0.0389% 627/1,613,666 alleles · rare exomes 521/1,461,636 · genomes 106/152,030 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.988%	101
Remaining individualsnot grpmax-eligible	0.17%	590
South Asian	0.0406%	2,461
African / African-American	0.0347%	2,882
Admixed American	0.005%	19,994
European (non-Finnish)	0.00102%	98,325

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.Arg353Pro
Coding: c.1058G>C
MANE Select: NM_020779
dbSNP: rs76623454
Type: single nucleotide variant
Location: chr2:19966860 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 4 PDB
Residue 353: a β-strand

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

Disease context

short-rib thoracic dysplasia 7 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cranioectodermal dysplasia 2

Similar variants

WDR35 p.Arg353His Uncertain significance ★★ ⚠ same residue
WDR35 c.1255+1G>A Pathogenic/Likely pathogenic ★★ same condition
WDR35 c.2415-2A>G Likely pathogenic ★★ same condition
WDR35 p.Arg332Ter Pathogenic ★★ same condition
WDR35 p.Arg461Ter Pathogenic ★★ same condition
WDR35 p.Arg564Ter Pathogenic/Likely pathogenic ★★ same condition
WDR35 p.Arg582Ter Pathogenic/Likely pathogenic ★★ same condition
WDR35 p.Gln46Ter Pathogenic/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/wdr35-p-arg353pro (accessed [today's date]).

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