Is PTCH2 p.Ser609Arg (c.1827C>A) pathogenic?

PTCH2 p.Ser609Arg (c.1827C>A) is classified Uncertain significance in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely benign (0.2813); Very rare (popmax 0.00666%, amr); Associated with medulloblastoma.

What condition is associated with PTCH2 p.Ser609Arg (c.1827C>A)?

PTCH2 p.Ser609Arg (c.1827C>A) is associated with medulloblastoma, basal cell carcinoma, susceptibility to, 1 (ClinVar).

How common is PTCH2 p.Ser609Arg (c.1827C>A) in the general population?

PTCH2 p.Ser609Arg (c.1827C>A) is very rare (popmax 0.00666%, amr) (gnomAD).

How is Medulloblastoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PTCH2 p.Ser609Arg (c.1827C>A)?

AlphaMissense predicts likely benign (score 0.2813) — an in-silico prediction, not a clinical call.

PTCH2 p.Ser609Arg

c.1827C>A · VCV3584541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

medulloblastoma

Computational evidence

Protein change
AlphaMissense	0.2813	likely benign
REVEL	0.439	indeterminate
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.00666% Admixed American · 4/60,030 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,614,112 alleles · very rare exomes 4/1,461,754 · genomes 0/152,358 · 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: PTCH2
Protein: p.Ser609Arg
Coding: c.1827C>A
MANE Select: NM_003738
Type: single nucleotide variant
Location: chr1:44828074 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25

Full PTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

medulloblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: basal cell carcinoma, susceptibility to, 1

For Medulloblastoma (Orphanet):

Inheritance: Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PTCH2 c.617+4A>T Uncertain significance ★★ same condition
PTCH2 p.Ala1090Val Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala371Gly Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala419Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala755Pro Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala935Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Arg175Trp Uncertain significance ★★ ⚠ same condition
PTCH2 p.Arg37Cys 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-ser609arg (accessed [today's date]).

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