Is CTSC p.Cys291Ser (c.872G>C) pathogenic?

CTSC p.Cys291Ser (c.872G>C) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-02). AlphaMissense: likely pathogenic (0.9628); Absent from gnomAD v4.1; Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Cys291Ser (c.872G>C)?

CTSC p.Cys291Ser (c.872G>C) is associated with Haim-Munk syndrome, Papillon-Lefevre disease, periodontitis, aggressive (ClinVar).

How common is CTSC p.Cys291Ser (c.872G>C) in the general population?

CTSC p.Cys291Ser (c.872G>C) is absent from gnomAD v4.1 (gnomAD).

How is Haim-Munk syndrome inherited?

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

What do computational predictors say about CTSC p.Cys291Ser (c.872G>C)?

AlphaMissense predicts likely pathogenic (score 0.9628) — an in-silico prediction, not a clinical call.

CTSC p.Cys291Ser

c.872G>C · rs748729285 · VCV942336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9628 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haim-Munk syndrome

Computational evidence

Protein change
AlphaMissense	0.9628	likely pathogenic · top 3% in CTSC
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -14.98	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	27.8	PHRED · no single calibrated threshold — expert panels disagree

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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSC
Protein: p.Cys291Ser
Coding: c.872G>C
MANE Select: NM_001814
dbSNP: rs748729285
Type: single nucleotide variant
Location: chr11:88296150 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 291: 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

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 p.Cys291Tyr Uncertain significance ★★ ⚠ same residue
CTSC p.Cys291= Likely benign ★ 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

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-cys291ser (accessed [today's date]).

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