Is PTCH1 p.Lys89Arg (c.266A>G) pathogenic?

PTCH1 p.Lys89Arg (c.266A>G) is classified Uncertain significance in PTCH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-30). AlphaMissense: likely benign (0.0675); Absent from gnomAD v4.1; Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH1 p.Lys89Arg (c.266A>G)?

PTCH1 p.Lys89Arg (c.266A>G) is associated with nevoid basal cell carcinoma syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTCH1 p.Lys89Arg (c.266A>G) in the general population?

PTCH1 p.Lys89Arg (c.266A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTCH1 p.Lys89Arg (c.266A>G)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

PTCH1 p.Lys89Arg

c.266A>G · rs1843661629 · VCV841933

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP -2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.78 · regional, not allelic
Overall
CADD	19.84	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.Lys89Arg
Coding: c.266A>G
MANE Select: NM_000264
dbSNP: rs1843661629
Type: single nucleotide variant
Location: chr9:95506535 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 89: an α-helix; the 'pre-tm1' region

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

Also linked: hereditary neoplastic syndrome

Similar variants

PTCH1 p.Lys89Asn Uncertain significance ★★ ⚠ same residue
PTCH1 p.Lys89Glu Uncertain significance ★ ⚠ 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-lys89arg (accessed [today's date]).

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