Is CTSK p.Glu43Ter (c.127G>T) pathogenic?

CTSK p.Glu43Ter (c.127G>T) is classified Likely pathogenic in CTSK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-30). Absent from gnomAD v4.1; Associated with pycnodysostosis.

What condition is associated with CTSK p.Glu43Ter (c.127G>T)?

CTSK p.Glu43Ter (c.127G>T) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Glu43Ter (c.127G>T) in the general population?

CTSK p.Glu43Ter (c.127G>T) is absent from gnomAD v4.1 (gnomAD).

How is Pycnodysostosis inherited?

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

CTSK p.Glu43Ter

c.127G>T · rs2525178878 · VCV1726256

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

pycnodysostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	Δ0.40	acceptor loss · deltas
Pangolin	Δ0.53	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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: CTSK
Protein: p.Glu43Ter
Coding: c.127G>T
MANE Select: NM_000396
dbSNP: rs2525178878
Type: single nucleotide variant
Location: chr1:150806218 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 43: an α-helix

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

CTSO p.Ala43Val 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
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-glu43ter (accessed [today's date]).

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