Is CTSB p.Pro181Leu (c.542C>T) pathogenic?

CTSB p.Pro181Leu (c.542C>T) is classified Uncertain significance in CTSB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.9126); Very rare (popmax 0.0038%, amr).

How common is CTSB p.Pro181Leu (c.542C>T) in the general population?

CTSB p.Pro181Leu (c.542C>T) is very rare (popmax 0.0038%, amr) (gnomAD).

What do computational predictors say about CTSB p.Pro181Leu (c.542C>T)?

AlphaMissense predicts likely pathogenic (score 0.9126) — an in-silico prediction, not a clinical call.

CTSB p.Pro181Leu

c.542C>T · VCV4235829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0038%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9126	likely pathogenic
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0038% Admixed American · 2/52,674 alleles

Filtering AF 0.00063% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000314%

Overall 0.00107% 17/1,594,606 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0038%	26,337
Remaining individualsnot grpmax-eligible	0.00324%	30,821
African / African-American	0.00272%	36,801
East Asian	0.00223%	44,772
European (non-Finnish)	0.000851%	117,460

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.Pro181Leu
Coding: c.542C>T
MANE Select: NM_001908
Type: single nucleotide variant
Location: chr8:11847813 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 181: a disulfide bond

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

Similar variants

CTSB p.Pro181= Likely benign ★ 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-pro181leu (accessed [today's date]).

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