Is CTSC p.Trp39Ser (c.116G>C) pathogenic?

CTSC p.Trp39Ser (c.116G>C) is classified Likely pathogenic in CTSC (ClinVar, Single submitter, 3 submitters; last evaluated 2025-02-15). AlphaMissense: likely pathogenic (0.9571); Very rare (popmax 0.00363%, amr); Associated with Papillon-Lefevre disease.

What condition is associated with CTSC p.Trp39Ser (c.116G>C)?

CTSC p.Trp39Ser (c.116G>C) is associated with Papillon-Lefevre disease, Haim-Munk syndrome, CTSC-related disorder (ClinVar).

How common is CTSC p.Trp39Ser (c.116G>C) in the general population?

CTSC p.Trp39Ser (c.116G>C) is very rare (popmax 0.00363%, amr) (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.Trp39Ser (c.116G>C)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

CTSC p.Trp39Ser

c.116G>C · rs104894210 · VCV7296

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00363%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Papillon-Lefevre disease

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic ✓ concordant with ClinVar · top 4% in CTSC
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -15.38	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 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	34.0	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 0.00363% Admixed American · 2/55,112 alleles

Filtering AF 0.000602% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000225%

Overall 0.00019% 3/1,576,786 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00363%	27,556
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,970

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: CTSC
Protein: p.Trp39Ser
Coding: c.116G>C
MANE Select: NM_001814
dbSNP: rs104894210
Type: single nucleotide variant
Location: chr11:88337557 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 39: 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 CTSC-related disorder 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.Trp39Cys 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-trp39ser (accessed [today's date]).

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