Is CTSC p.Lys216= (c.648A>G) pathogenic?

CTSC p.Lys216= (c.648A>G) is classified Likely benign in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). Rare (popmax 0.155%, sas); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Lys216= (c.648A>G)?

CTSC p.Lys216= (c.648A>G) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Lys216= (c.648A>G) in the general population?

CTSC p.Lys216= (c.648A>G) is rare (popmax 0.155%, sas) (gnomAD).

CTSC p.Lys216=

c.648A>G · rs551643961 · VCV1625718

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.155%, sas)

Conditions

periodontitis, aggressive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.048	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -1, phastCons 0.99
Overall
CADD	7.566	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.155% South Asian · 141/90,948 alleles

Filtering AF 0.134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.00939% 151/1,607,460 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.155%	645
Middle Eastern	0.0165%	6,044
Remaining individualsnot grpmax-eligible	0.00803%	12,458
European (non-Finnish)	0.000341%	293,488

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.Lys216=
Coding: c.648A>G
MANE Select: NM_001814
dbSNP: rs551643961
Type: single nucleotide variant
Location: chr11:88300639 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB

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.Lys216_Pro217delinsAsnTer Pathogenic ★ 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-lys216 (accessed [today's date]).

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