Is PTCH2 p.Ser728= (c.2184C>T) pathogenic?

PTCH2 p.Ser728= (c.2184C>T) is classified Likely benign in PTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0516%, amr); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Ser728= (c.2184C>T)?

PTCH2 p.Ser728= (c.2184C>T) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Ser728= (c.2184C>T) in the general population?

PTCH2 p.Ser728= (c.2184C>T) is ultra-rare (popmax 0.0516%, amr) (gnomAD).

PTCH2 p.Ser728=

c.2184C>T · rs146379791 · VCV524602

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, 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 2.8	GERP -2.8, phastCons 1
Overall
CADD	12.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% Admixed American · 31/60,032 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.0351% 567/1,614,058 alleles · ultra-rare exomes 514/1,461,752 · genomes 53/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0516%	1,937
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0392%	2,554
South Asian	0.0384%	2,603
Remaining individualsnot grpmax-eligible	0.0288%	3,472
African / African-American	0.0227%	4,415
Finnishnot grpmax-eligible	0.00156%	63,910

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.Ser728=
Coding: c.2184C>T
MANE Select: NM_003738
dbSNP: rs146379791
Type: single nucleotide variant
Location: chr1:44827589 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 728: 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.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-ser728 (accessed [today's date]).

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