Is CTSK p.Leu7Pro (c.20T>C) pathogenic?

CTSK p.Leu7Pro (c.20T>C) is classified Likely pathogenic in CTSK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.2811); Very rare (popmax 0.000339%, nfe); Associated with pycnodysostosis.

What condition is associated with CTSK p.Leu7Pro (c.20T>C)?

CTSK p.Leu7Pro (c.20T>C) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Leu7Pro (c.20T>C) in the general population?

CTSK p.Leu7Pro (c.20T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Pycnodysostosis inherited?

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

What do computational predictors say about CTSK p.Leu7Pro (c.20T>C)?

AlphaMissense predicts likely benign (score 0.2811) — an in-silico prediction, not a clinical call.

CTSK p.Leu7Pro

c.20T>C · rs1654101631 · VCV3241228

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pycnodysostosis

Computational evidence

Protein change
AlphaMissense	0.2811	likely benign ⚠ discordant with ClinVar
REVEL	0.743	pathogenic-leaning
SaProt	LLR -13.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 6.6e-08 · regional, not allelic
Overall
CADD	25.3	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 0.000339% European (non-Finnish) · 4/1,180,050 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,984 alleles · very rare

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: CTSK
Protein: p.Leu7Pro
Coding: c.20T>C
MANE Select: NM_000396
dbSNP: rs1654101631
Type: single nucleotide variant
Location: chr1:150806786 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB

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

Disease context

pycnodysostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pycnodysostosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CTSK p.Leu7= Likely benign ★★ same residue
CTSK c.121-1G>A Pathogenic/Likely pathogenic ★★ same condition
CTSK c.121-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSK c.244-29A>G Pathogenic/Likely pathogenic ★★ same condition
CTSK c.400-1G>C Likely pathogenic ★★ same condition
CTSK c.784+1G>A Likely pathogenic ★★ same condition
CTSK p.Ala277Val Pathogenic ★★ same condition
CTSK p.Arg122Ter 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/ctsk-p-leu7pro (accessed [today's date]).

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