Is PTCH1 p.Pro504Leu (c.1511C>T) pathogenic?

PTCH1 p.Pro504Leu (c.1511C>T) is classified Conflicting classifications of pathogenicity in PTCH1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-11). AlphaMissense: likely pathogenic (0.972); Absent from gnomAD v4.1; Associated with PTCH1-related disorder.

What condition is associated with PTCH1 p.Pro504Leu (c.1511C>T)?

PTCH1 p.Pro504Leu (c.1511C>T) is associated with PTCH1-related disorder, basal cell carcinoma, susceptibility to, 1, hereditary neoplastic syndrome (ClinVar).

How common is PTCH1 p.Pro504Leu (c.1511C>T) in the general population?

PTCH1 p.Pro504Leu (c.1511C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTCH1 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely pathogenic (score 0.972) — an in-silico prediction, not a clinical call.

PTCH1 p.Pro504Leu

c.1511C>T · rs1588598694 · VCV1774216

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTCH1-related disorder

Computational evidence

Protein change
AlphaMissense	0.972	likely pathogenic
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -15.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 8,917 bp · p 5.9e-10 · regional, not allelic
Overall
CADD	32.0	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

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.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_000264
dbSNP: rs1588598694
Type: single nucleotide variant
Location: chr9:95476850 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 504: an α-helix; the ssd domain

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

Disease context

PTCH1-related disorder

Also linked: basal cell carcinoma, susceptibility to, 1 hereditary neoplastic syndrome

Similar variants

PTCH1 p.Pro504= Likely benign ★★ same residue
PTCH1 p.Pro504Thr Uncertain significance ★ ⚠ same residue
PTCH1 p.Pro504Gln Likely pathogenic ★ 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.1348-2A>G Pathogenic ★★ same condition
PTCH1 c.1602+1G>T 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-pro504leu (accessed [today's date]).

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