Is CTSC p.Leu14= (c.40C>T) pathogenic?

CTSC p.Leu14= (c.40C>T) is classified Likely benign in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). Very rare (popmax 0.00807%, afr); Associated with Papillon-Lefevre disease.

What condition is associated with CTSC p.Leu14= (c.40C>T)?

CTSC p.Leu14= (c.40C>T) is associated with Papillon-Lefevre disease, Haim-Munk syndrome, periodontitis, aggressive (ClinVar).

How common is CTSC p.Leu14= (c.40C>T) in the general population?

CTSC p.Leu14= (c.40C>T) is very rare (popmax 0.00807%, afr) (gnomAD).

How is Papillon-Lefèvre syndrome inherited?

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

CTSC p.Leu14=

c.40C>T · rs943332293 · VCV1153399

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00807%, afr)

Conditions

Papillon-Lefevre disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.49, phastCons 1
Overall
CADD	10.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00807% African / African-American · 6/74,334 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0024%

Overall 0.000568% 9/1,584,554 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00807%	12,389
Admixed American	0.00358%	27,914
European (non-Finnish)	8.58e-05%	1,164,920

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.Leu14=
Coding: c.40C>T
MANE Select: NM_001814
dbSNP: rs943332293
Type: single nucleotide variant
Location: chr11:88337633 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB

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 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
CTSC p.Arg339Cys 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-leu14 (accessed [today's date]).

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