Is PTCH2 p.Pro209= (c.627G>A) pathogenic?

PTCH2 p.Pro209= (c.627G>A) is classified Likely benign in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Ultra-rare (popmax 0.0217%, amr); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Pro209= (c.627G>A)?

PTCH2 p.Pro209= (c.627G>A) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Pro209= (c.627G>A) in the general population?

PTCH2 p.Pro209= (c.627G>A) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

PTCH2 p.Pro209=

c.627G>A · rs373848645 · VCV453943

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6	GERP -3.8
Overall
CADD	2.057	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,930 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.0059% 95/1,610,928 alleles · ultra-rare exomes 81/1,458,738 · genomes 14/152,190 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
Admixed Americangrpmax	0.0217%	4,610
Remaining individualsnot grpmax-eligible	0.00804%	12,444
Finnishnot grpmax-eligible	0.00313%	31,948
European (non-Finnish)	0.00254%	39,304
East Asian	0.00223%	44,848
African / African-American	0.00134%	74,844

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro209=
Coding: c.627G>A
MANE Select: NM_003738
dbSNP: rs373848645
Type: single nucleotide variant
Location: chr1:44831034 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 209: 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.Pro209Leu Uncertain significance ★★ ⚠ same residue
PTCH2 p.Pro209Arg Uncertain significance ★ ⚠ 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-pro209 (accessed [today's date]).

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