Is CTSC p.Ala21= (c.63C>T) pathogenic?

CTSC p.Ala21= (c.63C>T) is classified Likely benign in CTSC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-21). Very rare (popmax 0.00577%, sas); Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Ala21= (c.63C>T)?

CTSC p.Ala21= (c.63C>T) is associated with Haim-Munk syndrome, Papillon-Lefevre disease, periodontitis, aggressive (ClinVar).

How common is CTSC p.Ala21= (c.63C>T) in the general population?

CTSC p.Ala21= (c.63C>T) is very rare (popmax 0.00577%, sas) (gnomAD).

How is Haim-Munk syndrome inherited?

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

CTSC p.Ala21=

c.63C>T · rs773560028 · VCV1935599

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00577%, sas)

Conditions

Haim-Munk syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -2.8
Overall
CADD	0.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00577% South Asian · 5/86,620 alleles

Filtering AF 0.00219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00063% 9/1,428,818 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00577%	17,324
European (non-Finnish)	0.000344%	290,770

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.Ala21=
Coding: c.63C>T
MANE Select: NM_001814
dbSNP: rs773560028
Type: single nucleotide variant
Location: chr11:88337610 (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

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.Ala21Val 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-ala21 (accessed [today's date]).

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