Is PTCH2 p.Ala755Pro (c.2263G>C) pathogenic?

PTCH2 p.Ala755Pro (c.2263G>C) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-22). AlphaMissense: likely benign (0.1442); Ultra-rare (popmax 0.0134%, eas); Associated with PTCH2-related disorder.

What condition is associated with PTCH2 p.Ala755Pro (c.2263G>C)?

PTCH2 p.Ala755Pro (c.2263G>C) is associated with PTCH2-related disorder, nevoid basal cell carcinoma syndrome, medulloblastoma (ClinVar).

How common is PTCH2 p.Ala755Pro (c.2263G>C) in the general population?

PTCH2 p.Ala755Pro (c.2263G>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about PTCH2 p.Ala755Pro (c.2263G>C)?

AlphaMissense predicts likely benign (score 0.1442) — an in-silico prediction, not a clinical call.

PTCH2 p.Ala755Pro

c.2263G>C · rs200862802 · VCV2084472

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1442 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PTCH2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1442	likely benign
REVEL	0.466	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.77, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,878 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000372% 6/1,614,032 alleles · ultra-rare exomes 5/1,461,790 · genomes 1/152,242 · 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.Ala755Pro
Coding: c.2263G>C
MANE Select: NM_003738
dbSNP: rs200862802
Type: single nucleotide variant
Location: chr1:44827510 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 755: the 'extracellular domain 2 (ecd2)' region

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

Disease context

PTCH2-related disorder

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

Similar variants

PTCH2 p.Ala755Thr 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-ala755pro (accessed [today's date]).

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