Is PTCH2 p.Pro522Ala (c.1564C>G) pathogenic?

PTCH2 p.Pro522Ala (c.1564C>G) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: ambiguous (0.5543); Absent from gnomAD v4.1.

How common is PTCH2 p.Pro522Ala (c.1564C>G) in the general population?

PTCH2 p.Pro522Ala (c.1564C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTCH2 p.Pro522Ala (c.1564C>G)?

AlphaMissense predicts ambiguous (score 0.5543) — an in-silico prediction, not a clinical call.

PTCH2 p.Pro522Ala

c.1564C>G · rs1222890965 · VCV2613100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5543 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5543	ambiguous
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -12.53	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 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTCH2
Protein: p.Pro522Ala
Coding: c.1564C>G
MANE Select: NM_003738
dbSNP: rs1222890965
Type: single nucleotide variant
Location: chr1:44828532 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 522: the ssd domain

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

Similar variants

PTCH2 p.Pro522Leu Uncertain significance ★ ⚠ same residue
PTCH2 p.Pro522= Likely benign ★ same residue
PTCH2 c.2976+2T>C Uncertain significance ★★ same type
PTCH2 c.526-2A>G Uncertain significance ★★ same type
PTCH2 c.617+4A>T Uncertain significance ★★ same type
PTCH2 c.618-6C>A Uncertain significance ★★ same type
PTCH2 p.Ala1052Thr Uncertain significance ★★ ⚠ same type
PTCH2 p.Ala1090Val Uncertain significance ★★ ⚠ same type

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-pro522ala (accessed [today's date]).

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