Is PTCH2 p.Arg397fs (c.1189del) pathogenic?

PTCH2 p.Arg397fs (c.1189del) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-23). Ultra-rare (popmax 0.0119%, nfe); Associated with basal cell carcinoma, susceptibility to, 1.

What condition is associated with PTCH2 p.Arg397fs (c.1189del)?

PTCH2 p.Arg397fs (c.1189del) is associated with basal cell carcinoma, susceptibility to, 1, nevoid basal cell carcinoma syndrome, medulloblastoma (ClinVar).

How common is PTCH2 p.Arg397fs (c.1189del) in the general population?

PTCH2 p.Arg397fs (c.1189del) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

PTCH2 p.Arg397fs

c.1189del · rs778199787 · VCV596587

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Conditions

basal cell carcinoma, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 0.75, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% European (non-Finnish) · 140/1,180,042 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00964%

Overall 0.00886% 143/1,614,066 alleles · ultra-rare exomes 136/1,461,882 · genomes 7/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,429
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00133%	74,918

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.Arg397fs
Coding: c.1189del
MANE Select: NM_003738
dbSNP: rs778199787
Type: Deletion
Location: chr1:44829428 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 397: the ssd domain

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

Disease context

basal cell carcinoma, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nevoid basal cell carcinoma syndrome medulloblastoma hereditary neoplastic syndrome

Similar variants

PTCH2 p.Arg397= Likely benign ★★ same residue
PTCH2 p.Arg397Cys Uncertain significance ★ ⚠ same residue
PTCH2 p.Arg397Gly Uncertain significance ★ ⚠ same residue
PTCH2 p.Asn508fs Uncertain significance ★★ same condition
PTCH2 p.Gly1197fs Uncertain significance ★★ same condition
PTCH2 p.Leu189fs Uncertain significance ★★ same condition
PTCH2 p.Leu443fs Uncertain significance ★★ same condition
PTCH2 p.Ser344fs 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-arg397fs (accessed [today's date]).

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