Is CTSC p.Leu7= (c.21G>A) pathogenic?

CTSC p.Leu7= (c.21G>A) is classified Likely benign in CTSC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-25). Ultra-rare (popmax 0.0229%, afr); Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Leu7= (c.21G>A)?

CTSC p.Leu7= (c.21G>A) is associated with Haim-Munk syndrome, Papillon-Lefevre disease, CTSC-related disorder (ClinVar).

How common is CTSC p.Leu7= (c.21G>A) in the general population?

CTSC p.Leu7= (c.21G>A) is ultra-rare (popmax 0.0229%, afr) (gnomAD).

How is Haim-Munk syndrome inherited?

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

CTSC p.Leu7=

c.21G>A · rs370256893 · VCV2922578

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, afr)

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 -0.5	GERP 0.52
Overall
CADD	4.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% African / African-American · 17/74,242 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.00114% 18/1,580,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0229%	4,367
Remaining individualsnot grpmax-eligible	0.00163%	61,244

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.Leu7=
Coding: c.21G>A
MANE Select: NM_001814
dbSNP: rs370256893
Type: single nucleotide variant
Location: chr11:88337652 (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 CTSC-related disorder periodontitis, aggressive

For Haim-Munk syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

CTSC p.Leu7Phe Uncertain significance ★ ⚠ same residue
CTSC p.Leu7fs Pathogenic ★ 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-leu7 (accessed [today's date]).

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