Is PTCH2 p.Pro17Ala (c.49C>G) pathogenic?

PTCH2 p.Pro17Ala (c.49C>G) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-13). AlphaMissense: likely benign (0.0521); Very rare (popmax 0.00274%, afr).

How common is PTCH2 p.Pro17Ala (c.49C>G) in the general population?

PTCH2 p.Pro17Ala (c.49C>G) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about PTCH2 p.Pro17Ala (c.49C>G)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

PTCH2 p.Pro17Ala

c.49C>G · rs994709304 · VCV2509342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.55, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	13.77	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 0.00274% African / African-American · 2/72,982 alleles

Filtering AF 0.000709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000554%

Overall 0.00103% 16/1,550,828 alleles · very rare exomes 15/1,398,626 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,491
European (non-Finnish)	0.00122%	81,899

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.Pro17Ala
Coding: c.49C>G
MANE Select: NM_003738
dbSNP: rs994709304
Type: single nucleotide variant
Location: chr1:44842884 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25

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

Similar variants

PTCH2 p.Pro17= Likely benign ★ same residue
PTCH2 p.Pro17fs Uncertain significance ★ 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-pro17ala (accessed [today's date]).

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