Is PAX3 p.Arg271Pro (c.812G>C) pathogenic?

PAX3 p.Arg271Pro (c.812G>C) is classified Pathogenic in PAX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-10). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with Waardenburg syndrome type 1.

What condition is associated with PAX3 p.Arg271Pro (c.812G>C)?

PAX3 p.Arg271Pro (c.812G>C) is associated with Waardenburg syndrome type 1 (ClinVar).

How common is PAX3 p.Arg271Pro (c.812G>C) in the general population?

PAX3 p.Arg271Pro (c.812G>C) is absent from gnomAD v4.1 (gnomAD).

How is Waardenburg syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PAX3 p.Arg271Pro (c.812G>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PAX3 p.Arg271Pro

c.812G>C · VCV4819380

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -16.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 94 kb · p 0.01 · regional, not allelic
Overall
CADD	31.0	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: PAX3
Protein: p.Arg271Pro
Coding: c.812G>C
MANE Select: NM_181458
Type: single nucleotide variant
Location: chr2:222221368 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 1 PDB
Residue 271: a DNA-binding region; a UniProt-annotated variant site (in ws1); an α-helix

Full PAX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Waardenburg syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Waardenburg syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PAX3 p.Arg271Cys Pathogenic ★★ same residue
PAX3 p.Arg271His Pathogenic ★★ same residue
PAX3 p.Arg271Gly Pathogenic ★ same residue
PAX3 c.452-1G>A Pathogenic/Likely pathogenic ★★ same condition
PAX3 c.793-1G>A Pathogenic ★★ same condition
PAX3 c.86-2A>C Pathogenic/Likely pathogenic ★★ same condition
PAX3 c.86-2A>G Pathogenic/Likely pathogenic ★★ same condition
PAX3 p.Arg223Gln 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/pax3-p-arg271pro (accessed [today's date]).

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