Is PTCH1 p.Ser356= (c.1068C>T) pathogenic?

PTCH1 p.Ser356= (c.1068C>T) is classified Conflicting classifications of pathogenicity in PTCH1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease.

What condition is associated with PTCH1 p.Ser356= (c.1068C>T)?

PTCH1 p.Ser356= (c.1068C>T) is associated with Charcot-Marie-Tooth disease, nevoid basal cell carcinoma syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTCH1 p.Ser356= (c.1068C>T) in the general population?

PTCH1 p.Ser356= (c.1068C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

PTCH1 p.Ser356=

c.1068C>T · rs1051875027 · VCV580752

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -3.8
Overall
CADD	0.577	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,613,886 alleles · very rare exomes 12/1,461,872 · genomes 2/152,014 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
African / African-American	0.00134%	74,856
European (non-Finnish)	0.00102%	98,334

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.Ser356=
Coding: c.1068C>T
MANE Select: NM_000264
dbSNP: rs1051875027
Type: single nucleotide variant
Location: chr9:95479147 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 356: 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

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nevoid basal cell carcinoma syndrome hereditary neoplastic syndrome

Similar variants

PTCH1 p.Ser356Asn 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
PTCH1 c.1348-2A>G Pathogenic ★★ same condition
PTCH1 c.1503+1G>C 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-ser356 (accessed [today's date]).

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