Is CTSC p.Arg272Pro (c.815G>C) pathogenic?

CTSC p.Arg272Pro (c.815G>C) is classified Pathogenic/Likely pathogenic in CTSC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-30). AlphaMissense: likely pathogenic (0.9806); Very rare (popmax 0.00878%, sas); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Arg272Pro (c.815G>C)?

CTSC p.Arg272Pro (c.815G>C) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Arg272Pro (c.815G>C) in the general population?

CTSC p.Arg272Pro (c.815G>C) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about CTSC p.Arg272Pro (c.815G>C)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

CTSC p.Arg272Pro

c.815G>C · rs587777534 · VCV548504

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic ✓ concordant with ClinVar · top 1% in CTSC
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -17.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	28.8	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 0.00878% South Asian · 8/91,078 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00459% 74/1,613,820 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,385
European (non-Finnish)	0.00559%	17,877

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.Arg272Pro
Coding: c.815G>C
MANE Select: NM_001814
dbSNP: rs587777534
Type: single nucleotide variant
Location: chr11:88296207 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 272: a disulfide bond; a UniProt-annotated variant site (in pls); 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.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same residue
CTSC p.Arg272Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CTSC p.Arg272Gly 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-arg272pro (accessed [today's date]).

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