Is PTCH2 p.Arg235Gln (c.704G>A) pathogenic?

PTCH2 p.Arg235Gln (c.704G>A) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.00535%, afr); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Arg235Gln (c.704G>A)?

PTCH2 p.Arg235Gln (c.704G>A) is associated with nevoid basal cell carcinoma syndrome, basal cell nevus syndrome 1 (ClinVar).

How common is PTCH2 p.Arg235Gln (c.704G>A) in the general population?

PTCH2 p.Arg235Gln (c.704G>A) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about PTCH2 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

PTCH2 p.Arg235Gln

c.704G>A · rs376337405 · VCV581418

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.82, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	23.7	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 0.00535% African / African-American · 4/74,826 alleles

Filtering AF 0.00403% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00429% 69/1,610,186 alleles · very rare exomes 60/1,458,038 · genomes 9/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,706
European (non-Finnish)	0.0051%	19,623
Remaining individualsnot grpmax-eligible	0.00482%	20,761
South Asian	0.0022%	45,467

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.Arg235Gln
Coding: c.704G>A
MANE Select: NM_003738
dbSNP: rs376337405
Type: single nucleotide variant
Location: chr1:44830957 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 235: 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

Also linked: basal cell nevus syndrome 1

Similar variants

PTCH2 p.Arg235Trp 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
PTCH2 p.Ala21Thr 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-arg235gln (accessed [today's date]).

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