Is CTSK p.Arg46Trp (c.136C>T) pathogenic?

CTSK p.Arg46Trp (c.136C>T) is classified Pathogenic/Likely pathogenic in CTSK (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-17). AlphaMissense: likely pathogenic (0.7386); Ultra-rare (popmax 0.0286%, sas); Associated with pycnodysostosis.

What condition is associated with CTSK p.Arg46Trp (c.136C>T)?

CTSK p.Arg46Trp (c.136C>T) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Arg46Trp (c.136C>T) in the general population?

CTSK p.Arg46Trp (c.136C>T) is ultra-rare (popmax 0.0286%, sas) (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.Arg46Trp (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.7386) — an in-silico prediction, not a clinical call.

CTSK p.Arg46Trp

c.136C>T · rs371277428 · VCV553560

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7386 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pycnodysostosis

Computational evidence

Protein change
AlphaMissense	0.7386	likely pathogenic ✓ concordant with ClinVar
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -14.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.31	acceptor loss · deltas
Pangolin	Δ0.31	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 6.6e-08 · regional, not allelic
Overall
CADD	32.0	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 0.0286% South Asian · 26/91,062 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00192% 31/1,613,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0286%	3,502
Remaining individualsnot grpmax-eligible	0.0032%	31,237
African / African-American	0.00134%	74,902
European (non-Finnish)	0.000169%	589,988

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.Arg46Trp
Coding: c.136C>T
MANE Select: NM_000396
dbSNP: rs371277428
Type: single nucleotide variant
Location: chr1:150806209 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 46: 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

CTSK p.Arg46Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg46trp (accessed [today's date]).

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