Is CTSC p.His127Pro (c.380A>C) pathogenic?

CTSC p.His127Pro (c.380A>C) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-27). AlphaMissense: likely pathogenic (0.967); Absent from gnomAD v4.1; Associated with Papillon-Lefevre disease.

What condition is associated with CTSC p.His127Pro (c.380A>C)?

CTSC p.His127Pro (c.380A>C) is associated with Papillon-Lefevre disease, Haim-Munk syndrome, periodontitis, aggressive (ClinVar).

How common is CTSC p.His127Pro (c.380A>C) in the general population?

CTSC p.His127Pro (c.380A>C) is absent from gnomAD v4.1 (gnomAD).

How is Papillon-Lefèvre syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSC p.His127Pro (c.380A>C)?

AlphaMissense predicts likely pathogenic (score 0.967) — an in-silico prediction, not a clinical call.

CTSC p.His127Pro

c.380A>C · rs104894216 · VCV7299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Papillon-Lefevre disease

Computational evidence

Protein change
AlphaMissense	0.967	likely pathogenic · top 3% in CTSC
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -15.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSC
Protein: p.His127Pro
Coding: c.380A>C
MANE Select: NM_001814
dbSNP: rs104894216
Type: single nucleotide variant
Location: chr11:88312493 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 127: a disulfide bond; a UniProt-annotated variant site (in pls); a β-strand

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

Disease context

Papillon-Lefevre disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Haim-Munk syndrome periodontitis, aggressive

For Papillon-Lefèvre syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CTSC p.His127Arg Uncertain significance ★★ ⚠ same residue
CTSC c.319-1G>A Pathogenic ★★ same condition
CTSC c.757+1G>T Likely pathogenic ★★ same condition
CTSC c.-55C>A Pathogenic ★★ same condition
CTSC p.Arg210Ter Pathogenic ★★ same condition
CTSC p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CTSC p.Arg272Pro Pathogenic/Likely 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/ctsc-p-his127pro (accessed [today's date]).

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