Is WAC p.Arg522Ser (c.1566A>T) pathogenic?

WAC p.Arg522Ser (c.1566A>T) is classified Uncertain significance in WAC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-29). AlphaMissense: likely pathogenic (0.8162); Absent from gnomAD v4.1.

How common is WAC p.Arg522Ser (c.1566A>T) in the general population?

WAC p.Arg522Ser (c.1566A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about WAC p.Arg522Ser (c.1566A>T)?

AlphaMissense predicts likely pathogenic (score 0.8162) — an in-silico prediction, not a clinical call.

WAC p.Arg522Ser

c.1566A>T · VCV3363591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8162 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8162	likely pathogenic
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.28	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.2	GERP -0.53, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 83 kb · p 0.6 · regional, not allelic
Overall
CADD	22.7	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: WAC
Protein: p.Arg522Ser
Coding: c.1566A>T
MANE Select: NM_016628
Type: single nucleotide variant
Location: chr10:28616182 (GRCh38)
Gene constraint: LOEUF 0.248 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.71
Residue 522: a UniProt-annotated variant site (found in a patient with severe intellectual disability; likely pathogenic); the 'disordered' region

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

Similar variants

WAC c.1437+1G>A Pathogenic/Likely pathogenic ★★ same type
WAC c.1746+2T>C Pathogenic ★★ same type
WAC c.381+1G>T Likely pathogenic ★★ same type
WAC p.Arg151Ter Pathogenic ★★ same type
WAC p.Arg47Ter Pathogenic ★★ same type
WAC p.Arg513Ter Pathogenic ★★ same type
WAC p.Arg550Ter Pathogenic ★★ same type
WAC p.Arg613Ter 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/wac-p-arg522ser (accessed [today's date]).

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