Is CTSC p.Ser209Arg (c.625A>C) pathogenic?

CTSC p.Ser209Arg (c.625A>C) is classified Uncertain significance in CTSC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-05). AlphaMissense: likely benign (0.1149); Ultra-rare (popmax 0.0107%, afr); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Ser209Arg (c.625A>C)?

CTSC p.Ser209Arg (c.625A>C) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Ser209Arg (c.625A>C) in the general population?

CTSC p.Ser209Arg (c.625A>C) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CTSC p.Ser209Arg (c.625A>C)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

CTSC p.Ser209Arg

c.625A>C · rs1216773092 · VCV2076974

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -1.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.8
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	6.515	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0107% African / African-American · 8/75,038 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000547% 8/1,461,676 alleles · ultra-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.Ser209Arg
Coding: c.625A>C
MANE Select: NM_001814
dbSNP: rs1216773092
Type: single nucleotide variant
Location: chr11:88309179 (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 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
CTSC p.Arg339Cys 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-ser209arg (accessed [today's date]).

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