Is CTSB p.Thr75Ala (c.223A>G) pathogenic?

CTSB p.Thr75Ala (c.223A>G) is classified Benign in CTSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-17). AlphaMissense: likely benign (0.0683); Low-frequency (popmax 1.76%, eas).

How common is CTSB p.Thr75Ala (c.223A>G) in the general population?

CTSB p.Thr75Ala (c.223A>G) is low-frequency (popmax 1.76%, eas) (gnomAD).

What do computational predictors say about CTSB p.Thr75Ala (c.223A>G)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

CTSB p.Thr75Ala

c.223A>G · rs74996838 · VCV1587655

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.76%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -7.44	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 2.1	GERP 0.6, phastCons 0.97
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	7.31	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 1.76% East Asian · 790/44,838 alleles

Filtering AF 1.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.62%

Overall 0.0737% 1,188/1,611,538 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.76%	57
Remaining individualsnot grpmax-eligible	0.192%	520
South Asian	0.116%	865
Ashkenazi Jewishnot grpmax-eligible	0.0982%	1,018
Admixed American	0.0685%	1,460
Middle Eastern	0.0661%	1,512
European (non-Finnish)	0.00798%	12,535
African / African-American	0.00667%	14,983

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.Thr75Ala
Coding: c.223A>G
MANE Select: NM_001908
dbSNP: rs74996838
Type: single nucleotide variant
Location: chr8:11850970 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB

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-thr75ala (accessed [today's date]).

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