Is PTCH1 p.Arg441Pro (c.1322G>C) pathogenic?

PTCH1 p.Arg441Pro (c.1322G>C) is classified Uncertain significance in PTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-31). AlphaMissense: likely pathogenic (0.9799); Very rare (popmax 0.0011%, sas); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH1 p.Arg441Pro (c.1322G>C)?

PTCH1 p.Arg441Pro (c.1322G>C) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH1 p.Arg441Pro (c.1322G>C) in the general population?

PTCH1 p.Arg441Pro (c.1322G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PTCH1 p.Arg441Pro (c.1322G>C)?

AlphaMissense predicts likely pathogenic (score 0.9799) — an in-silico prediction, not a clinical call.

PTCH1 p.Arg441Pro

c.1322G>C · rs767273237 · VCV1038589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.9799	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -13.27	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 3,923 bp · p 0.013 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Overall 6.2e-05% 1/1,614,166 alleles · very rare exomes 1/1,461,886 · genomes 0/152,280 · 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.Arg441Pro
Coding: c.1322G>C
MANE Select: NM_000264
dbSNP: rs767273237
Type: single nucleotide variant
Location: chr9:95478080 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 441: an α-helix; the ssd domain

Full PTCH1 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

PTCH1 p.Arg441Cys Uncertain significance ★★ ⚠ same residue
PTCH1 p.Arg441= Likely benign ★★ same residue
PTCH1 p.Arg441His Conflicting classifications of pathogenicity ★ ⚠ same residue
PTCH1 p.Arg441fs Pathogenic ★ same residue
PTCH1 p.Arg441Leu Uncertain significance ★ ⚠ same residue
PTCH1 c.1068-1G>A Pathogenic/Likely pathogenic ★★ same condition
PTCH1 c.1216-1G>A Pathogenic/Likely pathogenic ★★ same condition
PTCH1 c.1348-1G>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-arg441pro (accessed [today's date]).

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