Is CTSB p.Thr140= (c.420A>G) pathogenic?

CTSB p.Thr140= (c.420A>G) is classified Benign in CTSB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). Common (popmax 19.2%, afr) — too common for a highly-penetrant pathogenic allele.

CTSB p.Thr140=

Q: How common is CTSB p.Thr140= (c.420A>G) in the general population?

CTSB p.Thr140= (c.420A>G) is common (popmax 19.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.420A>G · rs13332 · VCV1164778

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 19.2%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.76, phastCons 1
Overall
CADD	8.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19.2% African / African-American · 14,411/75,004 alleles

Filtering AF 19% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.8%

Overall 3.24% 52,281/1,612,684 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	19.2%	5
Middle Eastern	7.81%	13
Ashkenazi Jewishnot grpmax-eligible	5.7%	18
Amishnot grpmax-eligible	4.06%	25
Remaining individualsnot grpmax-eligible	3.81%	26
Admixed American	3.11%	32
European (non-Finnish)	2.41%	42
South Asian	2.22%	45
Finnishnot grpmax-eligible	1.61%	62
East Asian	0.00669%	14,947

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.Thr140=
Coding: c.420A>G
MANE Select: NM_001908
dbSNP: rs13332
Type: single nucleotide variant
Location: chr8:11849072 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 140: a disulfide bond; an α-helix

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

Similar variants

CTSB p.Thr140Lys Uncertain significance ★ ⚠ same residue
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

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-thr140 (accessed [today's date]).

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