Is PTCH2 p.Ser391Phe (c.1172C>T) pathogenic?

PTCH2 p.Ser391Phe (c.1172C>T) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.8277); Absent from gnomAD v4.1; Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Ser391Phe (c.1172C>T)?

PTCH2 p.Ser391Phe (c.1172C>T) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Ser391Phe (c.1172C>T) in the general population?

PTCH2 p.Ser391Phe (c.1172C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTCH2 p.Ser391Phe (c.1172C>T)?

AlphaMissense predicts likely pathogenic (score 0.8277) — an in-silico prediction, not a clinical call.

PTCH2 p.Ser391Phe

c.1172C>T · rs1553165363 · VCV453920

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8277 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.8277	likely pathogenic
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -11.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	28.5	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

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: PTCH2
Protein: p.Ser391Phe
Coding: c.1172C>T
MANE Select: NM_003738
dbSNP: rs1553165363
Type: single nucleotide variant
Location: chr1:44829445 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 391: the 'extracellular domain 1 (ecd1)' region

Full PTCH2 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

PTCH2 c.2976+2T>C Uncertain significance ★★ same condition
PTCH2 c.526-2A>G Uncertain significance ★★ same condition
PTCH2 c.618-6C>A Uncertain significance ★★ same condition
PTCH2 p.Ala1052Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala1090Val Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala203Val Uncertain significance ★★ same condition
PTCH2 p.Ala21Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala371Gly Uncertain significance ★★ ⚠ 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/ptch2-p-ser391phe (accessed [today's date]).

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