Is PTCH1 p.Ser243Pro (c.727T>C) pathogenic?

PTCH1 p.Ser243Pro (c.727T>C) is classified Conflicting classifications of pathogenicity in PTCH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1324); Very rare (popmax 0.00221%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PTCH1 p.Ser243Pro (c.727T>C)?

PTCH1 p.Ser243Pro (c.727T>C) is associated with hereditary neoplastic syndrome, nevoid basal cell carcinoma syndrome, basal cell carcinoma, susceptibility to, 1 (ClinVar).

How common is PTCH1 p.Ser243Pro (c.727T>C) in the general population?

PTCH1 p.Ser243Pro (c.727T>C) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about PTCH1 p.Ser243Pro (c.727T>C)?

AlphaMissense predicts likely benign (score 0.1324) — an in-silico prediction, not a clinical call.

PTCH1 p.Ser243Pro

c.727T>C · rs372422922 · VCV219707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1324	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -2.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.3	GERP 0.56, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 3,923 bp · p 0.013 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% European (non-Finnish) · 26/1,178,732 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,612,666 alleles · very rare exomes 22/1,460,456 · genomes 4/152,210 · joint denominator

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: PTCH1
Protein: p.Ser243Pro
Coding: c.727T>C
MANE Select: NM_000264
dbSNP: rs372422922
Type: single nucleotide variant
Location: chr9:95481968 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 243: the 'extracellular domain 1 (ecd1)' region

Full PTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nevoid basal cell carcinoma syndrome basal cell carcinoma, susceptibility to, 1

Similar variants

PTCH1 p.Ser243Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
PTCH1 p.Ser243fs Pathogenic ★ same residue
PTCH1 c.1068-1G>A Pathogenic/Likely pathogenic ★★ same condition
PTCH1 c.1068-1G>T Likely pathogenic ★★ same condition
PTCH1 c.1216-1G>A Pathogenic/Likely pathogenic ★★ same condition
PTCH1 c.1347+1G>C Likely pathogenic ★★ same condition
PTCH1 c.1348-1G>A Pathogenic ★★ same condition
PTCH1 c.1348-2A>G Pathogenic ★★ 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/ptch1-p-ser243pro (accessed [today's date]).

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