Is CTSC p.Pro59Thr (c.175C>A) pathogenic?

CTSC p.Pro59Thr (c.175C>A) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: likely benign (0.073); Ultra-rare (popmax 0.0125%, sas); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Pro59Thr (c.175C>A)?

CTSC p.Pro59Thr (c.175C>A) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Pro59Thr (c.175C>A) in the general population?

CTSC p.Pro59Thr (c.175C>A) is ultra-rare (popmax 0.0125%, sas) (gnomAD).

What do computational predictors say about CTSC p.Pro59Thr (c.175C>A)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

CTSC p.Pro59Thr

c.175C>A · rs750685011 · VCV2939896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.7, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	17.3	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 0.0125% South Asian · 11/87,650 alleles

Filtering AF 0.00701% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0054%

Overall 0.00241% 38/1,579,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0125%	7,968
Admixed American	0.00687%	14,552
Remaining individualsnot grpmax-eligible	0.00326%	30,669
African / African-American	0.00277%	36,128
Finnishnot grpmax-eligible	0.00161%	62,038
European (non-Finnish)	0.00156%	64,308

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.Pro59Thr
Coding: c.175C>A
MANE Select: NM_001814
dbSNP: rs750685011
Type: single nucleotide variant
Location: chr11:88335080 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 59: a disulfide bond

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.Pro59Leu 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
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-pro59thr (accessed [today's date]).

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