Is WDR81 p.Pro459= (c.1377T>G) pathogenic?

WDR81 p.Pro459= (c.1377T>G) is classified Likely benign in WDR81 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-11). Very rare (popmax 0.000438%, nfe).

How common is WDR81 p.Pro459= (c.1377T>G) in the general population?

WDR81 p.Pro459= (c.1377T>G) is very rare (popmax 0.000438%, nfe) (gnomAD).

WDR81 p.Pro459=

c.1377T>G · VCV4932605

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000438%, nfe)

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 -0.34	GERP -3.3, phastCons 0.096
Overall
CADD	5.859	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000438% European (non-Finnish) · 5/1,142,772 alleles

Filtering AF 0.000128% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000388% 6/1,544,638 alleles · very rare exomes 6/1,392,352 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00167%	59,768
European (non-Finnish)grpmax	0.000438%	228,554

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: WDR81
Protein: p.Pro459=
Coding: c.1377T>G
MANE Select: NM_001163809
Type: single nucleotide variant
Location: chr17:1726336 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.23
Residue 459: the beach domain; the 'necessary and sufficient for the interaction with sqstm1' region

Full WDR81 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WDR81 p.Arg1333Ter Pathogenic/Likely pathogenic ★★ same type
WDR81 p.Arg1779Ter Pathogenic ★★ same type
WDR81 p.Arg397Ter Likely pathogenic ★★ same type
WDR81 p.Gln1096Ter Pathogenic ★★ same type
WDR81 p.Pro856Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
WDR81 p.Tyr1257Ter Pathogenic/Likely pathogenic ★★ same type
WDR81 p.Tyr1281Ter Pathogenic/Likely pathogenic ★★ same type
WDR81 p.Ala1015Thr Uncertain significance ★★ ⚠ 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/wdr81-p-pro459 (accessed [today's date]).

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