Is PTCH2 p.Pro255Arg (c.764C>G) pathogenic?

PTCH2 p.Pro255Arg (c.764C>G) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.3571); Very rare (popmax 0.0013%, nfe); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Pro255Arg (c.764C>G)?

PTCH2 p.Pro255Arg (c.764C>G) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Pro255Arg (c.764C>G) in the general population?

PTCH2 p.Pro255Arg (c.764C>G) is very rare (popmax 0.0013%, nfe) (gnomAD).

What do computational predictors say about PTCH2 p.Pro255Arg (c.764C>G)?

AlphaMissense predicts ambiguous (score 0.3571) — an in-silico prediction, not a clinical call.

PTCH2 p.Pro255Arg

c.764C>G · VCV4778635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0013%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.3571	ambiguous
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -13.36	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	26.7	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

Grpmax group 0.0013% European (non-Finnish) · 15/1,154,136 alleles

Filtering AF 0.00078% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000619%

Overall 0.00095% 15/1,578,306 alleles · very rare exomes 13/1,426,114 · genomes 2/152,192 · joint denominator

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.Pro255Arg
Coding: c.764C>G
MANE Select: NM_003738
Type: single nucleotide variant
Location: chr1:44830897 (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.Pro255Ala 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-pro255arg (accessed [today's date]).

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