Is CTSK p.Arg47His (c.140G>A) pathogenic?

CTSK p.Arg47His (c.140G>A) is classified Uncertain significance in CTSK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). AlphaMissense: likely benign (0.3278); Ultra-rare (popmax 0.0233%, amr).

How common is CTSK p.Arg47His (c.140G>A) in the general population?

CTSK p.Arg47His (c.140G>A) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about CTSK p.Arg47His (c.140G>A)?

AlphaMissense predicts likely benign (score 0.3278) — an in-silico prediction, not a clinical call.

CTSK p.Arg47His

c.140G>A · rs199909074 · VCV2144048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3278	likely benign
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 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 0.0233% Admixed American · 14/60,012 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00254% 41/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,287
East Asian	0.0134%	7,479
African / African-American	0.00267%	37,498
Finnishnot grpmax-eligible	0.00156%	63,974
European (non-Finnish)	0.00144%	69,409
South Asian	0.0011%	91,078

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.Arg47His
Coding: c.140G>A
MANE Select: NM_000396
dbSNP: rs199909074
Type: single nucleotide variant
Location: chr1:150806205 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 47: an α-helix

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

Similar variants

CTSK c.121-1G>A Pathogenic/Likely pathogenic ★★ same type
CTSK c.121-2A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-29A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-2A>C Likely pathogenic ★★ same type
CTSK c.400-1G>C Likely pathogenic ★★ same type
CTSK c.784+1G>A Likely pathogenic ★★ same type
CTSK p.Ala277Val Pathogenic ★★ same type
CTSK p.Arg122Ter Pathogenic/Likely pathogenic ★★ same type

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-arg47his (accessed [today's date]).

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