Is PAX3 p.Pro52= (c.156C>G) pathogenic?

PAX3 p.Pro52= (c.156C>G) is classified Benign in PAX3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-20). Low-frequency (popmax 3.02%, afr); Associated with Waardenburg syndrome.

What condition is associated with PAX3 p.Pro52= (c.156C>G)?

PAX3 p.Pro52= (c.156C>G) is associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome (ClinVar).

How common is PAX3 p.Pro52= (c.156C>G) in the general population?

PAX3 p.Pro52= (c.156C>G) is low-frequency (popmax 3.02%, afr) (gnomAD).

How is Waardenburg syndrome inherited?

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

PAX3 p.Pro52=

c.156C>G · rs28945092 · VCV226994

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.02%, afr)

Conditions

Waardenburg syndrome

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 4.1	GERP -0.55, phastCons 1
Overall
CADD	13.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.02% African / African-American · 2,265/74,928 alleles

Filtering AF 2.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.88%

Overall 0.236% 3,792/1,608,192 alleles · low-frequency exomes 2,320/1,455,816 · genomes 1,472/152,376 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.02%	33
South Asian	0.622%	161
Middle Eastern	0.397%	252
Admixed American	0.362%	276
Remaining individualsnot grpmax-eligible	0.293%	341
Ashkenazi Jewishnot grpmax-eligible	0.0475%	2,106
European (non-Finnish)	0.0445%	2,248
East Asian	0.009%	11,117
Finnishnot grpmax-eligible	0.00319%	31,330

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: PAX3
Protein: p.Pro52=
Coding: c.156C>G
MANE Select: NM_181458
dbSNP: rs28945092
Type: single nucleotide variant
Location: chr2:222297143 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 1 PDB
Residue 52: a DNA-binding region; the 'pai subdomain' region

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

Disease context

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

Also linked: craniofacial-deafness-hand syndrome

For Waardenburg syndrome (Orphanet):

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

Similar variants

PAX3 c.452-1G>A Pathogenic/Likely pathogenic ★★ same condition
PAX3 p.Arg223Gln Pathogenic ★★ same condition
PAX3 p.Arg271Cys Pathogenic ★★ same condition
PAX3 p.Arg271His Pathogenic ★★ same condition
PAX3 p.Arg56Leu Pathogenic/Likely pathogenic ★★ same condition
PAX3 p.Asn47Lys Likely pathogenic ★★ same condition
PAX3 p.Gly42Ser Likely pathogenic ★★ same condition
PAX3 p.Ser73Leu 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-pro52 (accessed [today's date]).

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