Is CTSC p.Val64fs (c.189dup) pathogenic?

CTSC p.Val64fs (c.189dup) is classified Pathogenic in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-29). Very rare (popmax 0.00374%, nfe); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Val64fs (c.189dup)?

CTSC p.Val64fs (c.189dup) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Val64fs (c.189dup) in the general population?

CTSC p.Val64fs (c.189dup) is very rare (popmax 0.00374%, nfe) (gnomAD).

CTSC p.Val64fs

c.189dup · rs766504984 · VCV2160925

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00374%, nfe)

Conditions

periodontitis, aggressive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00374% European (non-Finnish) · 43/1,150,268 alleles

Filtering AF 0.00282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0025%

Overall 0.00292% 46/1,577,656 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00374%	26,750
Remaining individualsnot grpmax-eligible	0.00326%	30,648
African / African-American	0.00137%	73,196

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.Val64fs
Coding: c.189dup
MANE Select: NM_001814
dbSNP: rs766504984
Type: Duplication
Location: chr11:88335065 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 64: a disulfide bond; a β-strand

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

Disease context

periodontitis, aggressive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Papillon-Lefevre disease Haim-Munk syndrome

Similar variants

CTSC p.Arg203Ter Pathogenic ★ same condition
CTSC p.Gln225fs Pathogenic ★ same condition
CTSC p.Thr186fs Pathogenic ★ same condition
CTSC p.Tyr170Ter Pathogenic ★ same condition
CTSC c.173-19dup Benign ★ same condition
CTSC c.318+9dup Benign ★ same condition
CTSC c.641+19dup Benign ★ same condition
CTSC c.757+9dup Benign ★ 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-val64fs (accessed [today's date]).

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