Is CTSB p.Arg20Thr (c.59G>C) pathogenic?

CTSB p.Arg20Thr (c.59G>C) is classified Conflicting classifications of pathogenicity in CTSB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0951); Rare (popmax 0.139%, amr).

How common is CTSB p.Arg20Thr (c.59G>C) in the general population?

CTSB p.Arg20Thr (c.59G>C) is rare (popmax 0.139%, amr) (gnomAD).

What do computational predictors say about CTSB p.Arg20Thr (c.59G>C)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

CTSB p.Arg20Thr

c.59G>C · rs776915596 · VCV1661022

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.587	indeterminate
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	1.17	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 0.139% Admixed American · 83/59,786 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.106%

Overall 0.00564% 91/1,612,838 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.139%	720
African / African-American	0.00805%	12,415
Remaining individualsnot grpmax-eligible	0.0016%	62,454
European (non-Finnish)	8.48e-05%	1,179,838

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: CTSB
Protein: p.Arg20Thr
Coding: c.59G>C
MANE Select: NM_001908
dbSNP: rs776915596
Type: single nucleotide variant
Location: chr8:11853396 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 20: a β-strand

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

Similar variants

CTSB p.Arg331Pro Uncertain significance ★★ ⚠ same type
CTSB p.Asp333Asn Uncertain significance ★★ ⚠ same type
CTSB p.Lys220Glu Uncertain significance ★★ ⚠ same type
CTSB p.Met73Thr Uncertain significance ★★ ⚠ same type
CTSB p.Thr332Ala Uncertain significance ★★ ⚠ same type
CTSB c.327+20C>T Benign ★★ same type
CTSB c.446+9G>C Benign ★★ same type
CTSB c.447-16G>C Benign ★★ 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/ctsb-p-arg20thr (accessed [today's date]).

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