Is PTCH2 p.Ala475= (c.1425G>A) pathogenic?

PTCH2 p.Ala475= (c.1425G>A) is classified Benign/Likely benign in PTCH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-01). Rare (popmax 0.255%, nfe); Associated with basal cell nevus syndrome 1.

What condition is associated with PTCH2 p.Ala475= (c.1425G>A)?

PTCH2 p.Ala475= (c.1425G>A) is associated with basal cell nevus syndrome 1, nevoid basal cell carcinoma syndrome, basal cell carcinoma, susceptibility to, 1 (ClinVar).

How common is PTCH2 p.Ala475= (c.1425G>A) in the general population?

PTCH2 p.Ala475= (c.1425G>A) is rare (popmax 0.255%, nfe) (gnomAD).

PTCH2 p.Ala475=

c.1425G>A · rs35851686 · VCV239554

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.255%, nfe)

Conditions

basal cell nevus syndrome 1

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 -0.74	GERP -3.5, phastCons 0.017
Overall
CADD	6.294	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.255% European (non-Finnish) · 2,962/1,161,800 alleles

Filtering AF 0.247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.244%

Overall 0.208% 3,286/1,578,544 alleles · rare exomes 3,060/1,426,286 · genomes 226/152,258 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.255%	392
Ashkenazi Jewishnot grpmax-eligible	0.214%	467
Remaining individualsnot grpmax-eligible	0.168%	595
Amishnot grpmax-eligible	0.11%	912
Middle Eastern	0.1%	1,000
Finnishnot grpmax-eligible	0.0925%	1,082
Admixed American	0.0777%	1,286
African / African-American	0.0404%	2,473
South Asian	0.0265%	3,775

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: PTCH2
Protein: p.Ala475=
Coding: c.1425G>A
MANE Select: NM_003738
dbSNP: rs35851686
Type: single nucleotide variant
Location: chr1:44829021 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 475: the ssd domain

Full PTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

basal cell nevus syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nevoid basal cell carcinoma syndrome basal cell carcinoma, susceptibility to, 1

Similar variants

PTCH2 p.Ala475Glu Uncertain significance ★ ⚠ same residue
PTCH2 c.2976+2T>C Uncertain significance ★★ same condition
PTCH2 c.526-2A>G Uncertain significance ★★ same condition
PTCH2 c.617+4A>T Uncertain significance ★★ same condition
PTCH2 c.618-6C>A Uncertain significance ★★ same condition
PTCH2 p.Ala1052Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala1090Val Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala203Val Uncertain significance ★★ 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/ptch2-p-ala475 (accessed [today's date]).

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