Is CTSC p.Thr275= (c.825C>T) pathogenic?

CTSC p.Thr275= (c.825C>T) is classified Benign/Likely benign in CTSC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.21%, nfe); Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Thr275= (c.825C>T)?

CTSC p.Thr275= (c.825C>T) is associated with Haim-Munk syndrome, Papillon-Lefevre disease, periodontitis, aggressive (ClinVar).

How common is CTSC p.Thr275= (c.825C>T) in the general population?

CTSC p.Thr275= (c.825C>T) is low-frequency (popmax 1.21%, nfe) (gnomAD).

How is Haim-Munk syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CTSC p.Thr275=

c.825C>T · rs2230081 · VCV466229

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.21%, nfe)

Conditions

Haim-Munk syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.016	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.008, phastCons 1
Overall
CADD	10.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.21% European (non-Finnish) · 14,253/1,179,900 alleles

Filtering AF 1.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.18%

Overall 1.03% 16,624/1,613,954 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.58%	63
European (non-Finnish)grpmax	1.21%	83
Remaining individualsnot grpmax-eligible	0.907%	110
Ashkenazi Jewishnot grpmax-eligible	0.618%	162
South Asian	0.313%	320
Admixed American	0.29%	345
Middle Eastern	0.181%	551
African / African-American	0.181%	551
East Asian	0.00223%	44,870

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr275=
Coding: c.825C>T
MANE Select: NM_001814
dbSNP: rs2230081
Type: single nucleotide variant
Location: chr11:88296197 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 275: a disulfide bond; a turn

Full CTSC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Haim-Munk syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Papillon-Lefevre disease periodontitis, aggressive

For Haim-Munk syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

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-thr275 (accessed [today's date]).

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