Is CTSK p.Arg312Ter (c.934C>T) pathogenic?

CTSK p.Arg312Ter (c.934C>T) is classified Pathogenic/Likely pathogenic in CTSK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-13). Very rare (popmax 0.00267%, afr); Associated with pycnodysostosis.

What condition is associated with CTSK p.Arg312Ter (c.934C>T)?

CTSK p.Arg312Ter (c.934C>T) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Arg312Ter (c.934C>T) in the general population?

CTSK p.Arg312Ter (c.934C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Pycnodysostosis inherited?

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

CTSK p.Arg312Ter

c.934C>T · rs375958814 · VCV371426

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

pycnodysostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.9	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

Grpmax group 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00062% 10/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,457
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000593%	168,573

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.Arg312Ter
Coding: c.934C>T
MANE Select: NM_000396
dbSNP: rs375958814
Type: single nucleotide variant
Location: chr1:150796855 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 312: a β-strand; a disulfide bond

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.Arg312Gln Uncertain significance ★★ ⚠ same residue
CTSK p.Arg312Gly Likely pathogenic ★ same residue
CTSK p.Arg312= 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

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-arg312ter (accessed [today's date]).

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