Is PTCH1 p.Ser489= (c.1467A>G) pathogenic?

PTCH1 p.Ser489= (c.1467A>G) is classified Likely benign in PTCH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-21). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with PTCH1 p.Ser489= (c.1467A>G)?

PTCH1 p.Ser489= (c.1467A>G) is associated with hereditary neoplastic syndrome, nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH1 p.Ser489= (c.1467A>G) in the general population?

PTCH1 p.Ser489= (c.1467A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

PTCH1 p.Ser489=

c.1467A>G · rs747623182 · VCV524626

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hereditary neoplastic syndrome

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 -0.12	GERP -3.2, phastCons 0.68
Overall
CADD	8.715	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,160 alleles · ultra-rare exomes 8/1,461,886 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.000593%	168,576

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.Ser489=
Coding: c.1467A>G
MANE Select: NM_000264
dbSNP: rs747623182
Type: single nucleotide variant
Location: chr9:95477583 (GRCh38)
Gene constraint: LOEUF 0.146 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.36 · 16 PDB
Residue 489: an α-helix; the ssd domain

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.Ser489Ala Uncertain significance ★ ⚠ 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-ser489 (accessed [today's date]).

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