Is PTCH2 p.Ala463Pro (c.1387G>C) pathogenic?

PTCH2 p.Ala463Pro (c.1387G>C) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-02). AlphaMissense: likely pathogenic (0.9388); Ultra-rare (popmax 0.0133%, sas); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Ala463Pro (c.1387G>C)?

PTCH2 p.Ala463Pro (c.1387G>C) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Ala463Pro (c.1387G>C) in the general population?

PTCH2 p.Ala463Pro (c.1387G>C) is ultra-rare (popmax 0.0133%, sas) (gnomAD).

What do computational predictors say about PTCH2 p.Ala463Pro (c.1387G>C)?

AlphaMissense predicts likely pathogenic (score 0.9388) — an in-silico prediction, not a clinical call.

PTCH2 p.Ala463Pro

c.1387G>C · rs767529534 · VCV644300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9388 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.9388	likely pathogenic · top 7% in PTCH2
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -15.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0133% South Asian · 12/90,354 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00597%

Overall 0.000808% 13/1,609,274 alleles · ultra-rare exomes 13/1,456,946 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0133%	7,529
European (non-Finnish)	8.49e-05%	1,177,752

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.Ala463Pro
Coding: c.1387G>C
MANE Select: NM_003738
dbSNP: rs767529534
Type: single nucleotide variant
Location: chr1:44829059 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 463: the ssd domain

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 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
PTCH2 p.Ala21Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala371Gly 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-ala463pro (accessed [today's date]).

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