Is PTCH2 p.Pro852fs (c.2553dup) pathogenic?

PTCH2 p.Pro852fs (c.2553dup) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). Very rare (popmax 0.00534%, nfe); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Pro852fs (c.2553dup)?

PTCH2 p.Pro852fs (c.2553dup) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Pro852fs (c.2553dup) in the general population?

PTCH2 p.Pro852fs (c.2553dup) is very rare (popmax 0.00534%, nfe) (gnomAD).

PTCH2 p.Pro852fs

c.2553dup · rs748351060 · VCV2151579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Conditions

nevoid basal cell carcinoma syndrome

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 17 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.5	GERP -0.44, phastCons 1
Overall
CADD	32.0	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 0.00534% European (non-Finnish) · 63/1,180,030 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00514% 83/1,613,990 alleles · very rare exomes 81/1,461,796 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.024%	4,166
Finnishnot grpmax-eligible	0.00782%	12,792
European (non-Finnish)grpmax	0.00534%	18,731

Remaining individuals 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.Pro852fs
Coding: c.2553dup
MANE Select: NM_003738
dbSNP: rs748351060
Type: Duplication
Location: chr1:44827043 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 852: the 'extracellular domain 2 (ecd2)' 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.1685_1709+14dup Uncertain significance ★ same condition
PTCH2 p.Ala131fs Uncertain significance ★ same condition
PTCH2 p.Asn509fs Uncertain significance ★ same condition
PTCH2 p.Gln271fs Uncertain significance ★ same condition
PTCH2 p.Leu221fs Uncertain significance ★ same condition
PTCH2 p.Leu524fs Uncertain significance ★ same condition
PTCH2 p.Leu736fs Uncertain significance ★ same condition
PTCH2 p.Leu869fs 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-pro852fs (accessed [today's date]).

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