Is CTSC p.Phe374fs (c.1122del) pathogenic?

CTSC p.Phe374fs (c.1122del) is classified Pathogenic in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). Very rare (popmax 8.47e-05%, nfe); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Phe374fs (c.1122del)?

CTSC p.Phe374fs (c.1122del) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Phe374fs (c.1122del) in the general population?

CTSC p.Phe374fs (c.1122del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CTSC p.Phe374fs

c.1122del · rs1944274161 · VCV2935808

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 0.003, phastCons 1
Overall
CADD	25.4	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 0.000657% 1/152,100 alleles · very rare

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.Phe374fs
Coding: c.1122del
MANE Select: NM_001814
dbSNP: rs1944274161
Type: Deletion
Location: chr11:88294276 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 374: 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.Phe374Ser Uncertain significance ★ ⚠ same residue
CTSC p.Leu381fs Pathogenic ★★ same condition
CTSC p.Lys63_Val64insTer Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Thr189fs Pathogenic ★★ same condition
CTSC c.173-7del Benign/Likely benign ★★ same condition
CTSC c.486-25_492del Likely pathogenic ★ same condition
CTSC p.Ala417fs Pathogenic ★ same condition
CTSC p.Asp236fs 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-phe374fs (accessed [today's date]).

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