Is CTSK p.Ala277Val (c.830C>T) pathogenic?

CTSK p.Ala277Val (c.830C>T) is classified Pathogenic in CTSK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-30). AlphaMissense: likely pathogenic (0.9527); Ultra-rare (popmax 0.0111%, eas); Associated with CTSK-related disorder.

What condition is associated with CTSK p.Ala277Val (c.830C>T)?

CTSK p.Ala277Val (c.830C>T) is associated with CTSK-related disorder, pycnodysostosis (ClinVar).

How common is CTSK p.Ala277Val (c.830C>T) in the general population?

CTSK p.Ala277Val (c.830C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CTSK p.Ala277Val (c.830C>T)?

AlphaMissense predicts likely pathogenic (score 0.9527) — an in-silico prediction, not a clinical call.

CTSK p.Ala277Val

c.830C>T · rs74315304 · VCV8423

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9527 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CTSK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9527	likely pathogenic ✓ concordant with ClinVar
REVEL	0.674	pathogenic-leaning
SaProt	LLR -11.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.49	acceptor loss · deltas
Pangolin	Δ0.32	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 6.6e-08 · regional, not allelic
Overall
CADD	25.8	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 0.0111% East Asian · 5/44,870 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0011% 16/1,460,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,974
South Asian	0.0022%	45,522
Remaining individualsnot grpmax-eligible	0.0016%	62,472
Finnishnot grpmax-eligible	0.00156%	64,016
African / African-American	0.00133%	75,010
European (non-Finnish)	0.000509%	196,447

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.Ala277Val
Coding: c.830C>T
MANE Select: NM_000396
dbSNP: rs74315304
Type: single nucleotide variant
Location: chr1:150799228 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 277: a UniProt-annotated variant site (in pknd); a β-strand; a disulfide bond

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

Disease context

CTSK-related disorder

Also linked: pycnodysostosis

Similar variants

CTSK p.Ala277= 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.Arg122Ter Pathogenic/Likely pathogenic ★★ same condition
CTSK p.Arg241Ter 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-ala277val (accessed [today's date]).

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