Is CTSK p.Pro228= (c.684C>T) pathogenic?

CTSK p.Pro228= (c.684C>T) is classified Conflicting classifications of pathogenicity in CTSK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0692%, nfe); Associated with pycnodysostosis.

What condition is associated with CTSK p.Pro228= (c.684C>T)?

CTSK p.Pro228= (c.684C>T) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Pro228= (c.684C>T) in the general population?

CTSK p.Pro228= (c.684C>T) is ultra-rare (popmax 0.0692%, nfe) (gnomAD).

How is Pycnodysostosis inherited?

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

CTSK p.Pro228=

c.684C>T · rs142097792 · VCV292582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, nfe)

Conditions

pycnodysostosis

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 -5.1	GERP -3.9
Overall
CADD	5.519	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% European (non-Finnish) · 816/1,179,972 alleles

Filtering AF 0.0651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.0578% 933/1,613,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0692%	1,446
Remaining individualsnot grpmax-eligible	0.0688%	1,453
Admixed American	0.0383%	2,608
Finnishnot grpmax-eligible	0.025%	4,001
South Asian	0.0242%	4,140
African / African-American	0.0174%	5,759

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.Pro228=
Coding: c.684C>T
MANE Select: NM_000396
dbSNP: rs142097792
Type: single nucleotide variant
Location: chr1:150799644 (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.Pro228Thr Uncertain significance ⚠ same residue
CTSK p.Pro228Ser Uncertain significance ★ ⚠ 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

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-pro228 (accessed [today's date]).

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