Is CTSB p.Leu26Val (c.76C>G) pathogenic?

CTSB p.Leu26Val (c.76C>G) is classified Benign in CTSB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.153); Common (popmax 50.1%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CTSB p.Leu26Val (c.76C>G)?

AlphaMissense predicts likely benign (score 0.153) — an in-silico prediction, not a clinical call.

CTSB p.Leu26Val

Q: How common is CTSB p.Leu26Val (c.76C>G) in the general population?

CTSB p.Leu26Val (c.76C>G) is common (popmax 50.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.76C>G · rs12338 · VCV1168281

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.153 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 50.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.153	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -9.31	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 2.9	GERP 0.48, phastCons 1
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	17.08	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 50.1% East Asian · 22,428/44,742 alleles

Filtering AF 49.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.4%

Overall 38.3% 616,677/1,611,564 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	50.1%	2
Amishnot grpmax-eligible	46%	2
Finnishnot grpmax-eligible	39.6%	3
European (non-Finnish)	38.7%	3
Remaining individualsnot grpmax-eligible	38.5%	3
Admixed American	35.8%	3
South Asian	35.5%	3
Middle Eastern	34.7%	3
African / African-American	32.8%	3
Ashkenazi Jewishnot grpmax-eligible	29.1%	3

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.Leu26Val
Coding: c.76C>G
MANE Select: NM_001908
dbSNP: rs12338
Type: single nucleotide variant
Location: chr8:11853379 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 26: a UniProt-annotated variant site (in)

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

Similar variants

CTSB p.Leu26Pro Benign ★★ same residue
CTSB p.Leu26Arg Uncertain significance ★ ⚠ same residue
CTSB p.Leu26Met Uncertain significance ★ ⚠ same residue
CTSB p.Leu26fs 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

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-leu26val (accessed [today's date]).

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