Is CTSB p.Pro91Leu (c.272C>T) pathogenic?

CTSB p.Pro91Leu (c.272C>T) is classified Benign/Likely benign in CTSB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.2009); Low-frequency (popmax 1.1%, afr).

How common is CTSB p.Pro91Leu (c.272C>T) in the general population?

CTSB p.Pro91Leu (c.272C>T) is low-frequency (popmax 1.1%, afr) (gnomAD).

What do computational predictors say about CTSB p.Pro91Leu (c.272C>T)?

AlphaMissense predicts likely benign (score 0.2009) — an in-silico prediction, not a clinical call.

CTSB p.Pro91Leu

c.272C>T · rs11548596 · VCV732968

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2009 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.1%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2009	likely benign
REVEL	0.714	pathogenic-leaning
SaProt	LLR -13.49	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	26.9	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 1.1% African / African-American · 825/74,998 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.0633% 1,022/1,613,550 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.1%	91
Remaining individualsnot grpmax-eligible	0.0945%	1,059
Admixed American	0.0834%	1,200
Middle Eastern	0.0495%	2,020
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,226
Finnishnot grpmax-eligible	0.00625%	16,002
European (non-Finnish)	0.00602%	16,615
South Asian	0.0033%	30,345

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.Pro91Leu
Coding: c.272C>T
MANE Select: NM_001908
dbSNP: rs11548596
Type: single nucleotide variant
Location: chr8:11850921 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 91: a UniProt-annotated variant site (in)

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

Similar variants

CTSB p.Pro91Ser 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-pro91leu (accessed [today's date]).

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