Is CTSC p.Tyr294Cys (c.881A>G) pathogenic?

CTSC p.Tyr294Cys (c.881A>G) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: likely pathogenic (0.8211); Absent from gnomAD v4.1; Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Tyr294Cys (c.881A>G)?

CTSC p.Tyr294Cys (c.881A>G) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Tyr294Cys (c.881A>G) in the general population?

CTSC p.Tyr294Cys (c.881A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSC p.Tyr294Cys (c.881A>G)?

AlphaMissense predicts likely pathogenic (score 0.8211) — an in-silico prediction, not a clinical call.

CTSC p.Tyr294Cys

c.881A>G · rs2496532692 · VCV2004051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8211 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.8211	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -15.85	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	28.1	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.Tyr294Cys
Coding: c.881A>G
MANE Select: NM_001814
dbSNP: rs2496532692
Type: single nucleotide variant
Location: chr11:88296141 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 294: a disulfide bond; a UniProt-annotated variant site (in pls)

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.Tyr294= Likely benign ★ 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-tyr294cys (accessed [today's date]).

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