Is PTCH1 p.Phe259= (c.777C>T) pathogenic?

PTCH1 p.Phe259= (c.777C>T) is classified Conflicting classifications of pathogenicity in PTCH1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-08). Very rare (popmax 0.00119%, nfe); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH1 p.Phe259= (c.777C>T)?

PTCH1 p.Phe259= (c.777C>T) is associated with nevoid basal cell carcinoma syndrome, holoprosencephaly 7, hereditary neoplastic syndrome (ClinVar).

How common is PTCH1 p.Phe259= (c.777C>T) in the general population?

PTCH1 p.Phe259= (c.777C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

PTCH1 p.Phe259=

c.777C>T · rs750313305 · VCV415493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.348	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP -0.51, phastCons 1
Overall
CADD	14.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,890 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00093% 15/1,613,344 alleles · very rare exomes 14/1,461,824 · genomes 1/151,520 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,278
South Asian	0.0011%	90,982

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.Phe259=
Coding: c.777C>T
MANE Select: NM_000264
dbSNP: rs750313305
Type: single nucleotide variant
Location: chr9:95480558 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 259: the 'extracellular domain 1 (ecd1)' 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: holoprosencephaly 7 hereditary neoplastic syndrome

Similar variants

PTCH1 p.Phe259fs Pathogenic ★ 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-phe259 (accessed [today's date]).

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