Is PTCH2 p.Pro255Ala (c.763C>G) pathogenic?

PTCH2 p.Pro255Ala (c.763C>G) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.1553); Ultra-rare (popmax 0.0202%, afr); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Pro255Ala (c.763C>G)?

PTCH2 p.Pro255Ala (c.763C>G) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Pro255Ala (c.763C>G) in the general population?

PTCH2 p.Pro255Ala (c.763C>G) is ultra-rare (popmax 0.0202%, afr) (gnomAD).

What do computational predictors say about PTCH2 p.Pro255Ala (c.763C>G)?

AlphaMissense predicts likely benign (score 0.1553) — an in-silico prediction, not a clinical call.

PTCH2 p.Pro255Ala

c.763C>G · rs200618779 · VCV1404616

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1553 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.1553	likely benign
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -9.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	25.8	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

Grpmax group 0.0202% African / African-American · 15/74,368 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00996%

Overall 0.00139% 22/1,578,308 alleles · ultra-rare exomes 19/1,426,026 · genomes 3/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0202%	4,958
Middle Eastern	0.0175%	5,702
Remaining individualsnot grpmax-eligible	0.00658%	15,190
Admixed American	0.00172%	58,274
European (non-Finnish)	8.67e-05%	1,153,994

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.Pro255Ala
Coding: c.763C>G
MANE Select: NM_003738
dbSNP: rs200618779
Type: single nucleotide variant
Location: chr1:44830898 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 255: the 'extracellular domain 1 (ecd1)' region

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

Disease context

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

Similar variants

PTCH2 p.Pro255Arg Uncertain significance ★ ⚠ same residue
PTCH2 p.Pro255= Likely benign ★ same residue
PTCH2 c.2976+2T>C Uncertain significance ★★ same condition
PTCH2 c.526-2A>G 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-pro255ala (accessed [today's date]).

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