Is CTSC p.Ala449Val (c.1346C>T) pathogenic?

CTSC p.Ala449Val (c.1346C>T) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-30). AlphaMissense: ambiguous (0.43); Very rare (popmax 0.00267%, afr); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Ala449Val (c.1346C>T)?

CTSC p.Ala449Val (c.1346C>T) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Ala449Val (c.1346C>T) in the general population?

CTSC p.Ala449Val (c.1346C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CTSC p.Ala449Val (c.1346C>T)?

AlphaMissense predicts ambiguous (score 0.43) — an in-silico prediction, not a clinical call.

CTSC p.Ala449Val

c.1346C>T · rs1248449287 · VCV851940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.43 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.43	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -7.00	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.88, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	25.0	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 0.00267% African / African-American · 2/74,834 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00124% 20/1,613,784 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,417
Admixed American	0.00167%	59,944
European (non-Finnish)	0.00144%	69,411

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.Ala449Val
Coding: c.1346C>T
MANE Select: NM_001814
dbSNP: rs1248449287
Type: single nucleotide variant
Location: chr11:88294052 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 449: an α-helix

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.Ala449Thr Uncertain significance ★ ⚠ same residue
CTSC p.Ala449fs Uncertain significance ★★ same residue
CTSC p.Ala449Ser Uncertain significance ★ ⚠ 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

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-ala449val (accessed [today's date]).

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