Is CTSC p.Arg440Gln (c.1319G>A) pathogenic?

CTSC p.Arg440Gln (c.1319G>A) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely benign (0.1269); Ultra-rare (popmax 0.0495%, mid); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Arg440Gln (c.1319G>A)?

CTSC p.Arg440Gln (c.1319G>A) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Arg440Gln (c.1319G>A) in the general population?

CTSC p.Arg440Gln (c.1319G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CTSC p.Arg440Gln (c.1319G>A)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

CTSC p.Arg440Gln

c.1319G>A · rs140086884 · VCV2169560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.715	pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.87, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	25.3	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00341% 55/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.005%	19,985
European (non-Finnish)	0.00331%	30,257
East Asian	0.00223%	44,884
Finnishnot grpmax-eligible	0.00156%	63,982
South Asian	0.0011%	91,070

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.Arg440Gln
Coding: c.1319G>A
MANE Select: NM_001814
dbSNP: rs140086884
Type: single nucleotide variant
Location: chr11:88294079 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 440: 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.Arg440Trp Uncertain significance ★ ⚠ same residue
CTSC p.Arg440= 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

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-arg440gln (accessed [today's date]).

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