Is PTCH1 p.Pro299Ser (c.895C>T) pathogenic?

PTCH1 p.Pro299Ser (c.895C>T) is classified Conflicting classifications of pathogenicity in PTCH1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.3638); Very rare (popmax 0.00662%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PTCH1 p.Pro299Ser (c.895C>T)?

PTCH1 p.Pro299Ser (c.895C>T) is associated with hereditary neoplastic syndrome, nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH1 p.Pro299Ser (c.895C>T) in the general population?

PTCH1 p.Pro299Ser (c.895C>T) is very rare (popmax 0.00662%, sas) (gnomAD).

What do computational predictors say about PTCH1 p.Pro299Ser (c.895C>T)?

AlphaMissense predicts ambiguous (score 0.3638) — an in-silico prediction, not a clinical call.

PTCH1 p.Pro299Ser

c.895C>T · rs745669231 · VCV237504

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00662%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3638	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -13.20	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 3,923 bp · p 0.013 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 0.00662% South Asian · 6/90,578 alleles

Filtering AF 0.00288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.00062% 10/1,611,632 alleles · very rare exomes 10/1,461,872 · genomes 0/149,760 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00662%	15,096
Remaining individualsnot grpmax-eligible	0.0032%	31,226
Admixed American	0.00168%	59,574
European (non-Finnish)	8.48e-05%	1,179,677

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.Pro299Ser
Coding: c.895C>T
MANE Select: NM_000264
dbSNP: rs745669231
Type: single nucleotide variant
Location: chr9:95480440 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 299: a β-strand; the 'extracellular domain 1 (ecd1)' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nevoid basal cell carcinoma syndrome

Similar variants

PTCH1 p.Pro299Gln Uncertain significance ★★ ⚠ same residue
PTCH1 p.Pro299= Likely benign ★★ same residue
PTCH1 p.Pro299Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro299ser (accessed [today's date]).

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