Is PTCH1 p.Pro253Ser (c.757C>T) pathogenic?

PTCH1 p.Pro253Ser (c.757C>T) is classified Uncertain significance in PTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-19). AlphaMissense: likely benign (0.1164); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PTCH1 p.Pro253Ser (c.757C>T)?

PTCH1 p.Pro253Ser (c.757C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PTCH1 p.Pro253Ser (c.757C>T) in the general population?

PTCH1 p.Pro253Ser (c.757C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTCH1 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

PTCH1 p.Pro253Ser

c.757C>T · rs2118428333 · VCV2449664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -9.15	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 12	GERP 0.89, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 3,923 bp · p 0.013 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTCH1
Protein: p.Pro253Ser
Coding: c.757C>T
MANE Select: NM_000264
dbSNP: rs2118428333
Type: single nucleotide variant
Location: chr9:95480578 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 253: a β-strand; 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

Similar variants

PTCH1 p.Pro253Leu Uncertain significance ★ ⚠ same residue
PTCH1 p.Pro253= Likely benign ★ same residue
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.202-2A>C Pathogenic/Likely pathogenic ★★ same condition
PTCH1 c.202-2A>G Pathogenic ★★ same condition
PTCH1 c.394+1G>A 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-pro253ser (accessed [today's date]).

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