Is CTSB p.Leu30Val (c.88C>G) pathogenic?

CTSB p.Leu30Val (c.88C>G) is classified Conflicting classifications of pathogenicity in CTSB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.1235); Rare (popmax 0.137%, afr).

How common is CTSB p.Leu30Val (c.88C>G) in the general population?

CTSB p.Leu30Val (c.88C>G) is rare (popmax 0.137%, afr) (gnomAD).

What do computational predictors say about CTSB p.Leu30Val (c.88C>G)?

AlphaMissense predicts likely benign (score 0.1235) — an in-silico prediction, not a clinical call.

CTSB p.Leu30Val

c.88C>G · rs139053473 · VCV1654518

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1235 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.137%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1235	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	16.55	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 0.137% African / African-American · 102/74,698 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.00682% 110/1,613,274 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.137%	732
Admixed American	0.00668%	14,968
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	8.48e-05%	1,179,878

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.Leu30Val
Coding: c.88C>G
MANE Select: NM_001908
dbSNP: rs139053473
Type: single nucleotide variant
Location: chr8:11853367 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 30: an α-helix

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-leu30val (accessed [today's date]).

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