Is CTSC p.Leu409Val (c.1225C>G) pathogenic?

CTSC p.Leu409Val (c.1225C>G) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-10). AlphaMissense: likely benign (0.1152); Very rare (popmax 0.00891%, eas); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Leu409Val (c.1225C>G)?

CTSC p.Leu409Val (c.1225C>G) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Leu409Val (c.1225C>G) in the general population?

CTSC p.Leu409Val (c.1225C>G) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CTSC p.Leu409Val (c.1225C>G)?

AlphaMissense predicts likely benign (score 0.1152) — an in-silico prediction, not a clinical call.

CTSC p.Leu409Val

c.1225C>G · rs1380414024 · VCV2004532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.1152	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	22.4	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 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000274% 4/1,461,848 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.Leu409Val
Coding: c.1225C>G
MANE Select: NM_001814
dbSNP: rs1380414024
Type: single nucleotide variant
Location: chr11:88294173 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 409: 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.Leu409= 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-leu409val (accessed [today's date]).

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