Is PTCH2 p.Ala685= (c.2055T>C) pathogenic?

PTCH2 p.Ala685= (c.2055T>C) is classified Benign in PTCH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 59.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Ala685= (c.2055T>C)?

PTCH2 p.Ala685= (c.2055T>C) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

PTCH2 p.Ala685=

Q: How common is PTCH2 p.Ala685= (c.2055T>C) in the general population?

PTCH2 p.Ala685= (c.2055T>C) is common (popmax 59.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2055T>C · rs7525308 · VCV1166505

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 59.1%, afr) — too common for a highly-penetrant pathogenic allele

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 7.5	GERP -1, phastCons 1
Overall
CADD	10.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.1% African / African-American · 44,364/75,010 alleles

Filtering AF 58.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 58.5%

Overall 37.1% 598,717/1,613,718 alleles · common exomes 534,205/1,461,504 · genomes 64,512/152,214 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	59.1%	2
East Asian	49.9%	2
Admixed American	41.4%	2
Remaining individualsnot grpmax-eligible	37.2%	3
Finnishnot grpmax-eligible	35.7%	3
South Asian	35.6%	3
European (non-Finnish)	35.4%	3
Amishnot grpmax-eligible	33%	3
Ashkenazi Jewishnot grpmax-eligible	32%	3
Middle Eastern	27.5%	4

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.Ala685=
Coding: c.2055T>C
MANE Select: NM_003738
dbSNP: rs7525308
Type: single nucleotide variant
Location: chr1:44827846 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 685: the 'pre-tm7' 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 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-ala685 (accessed [today's date]).

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