Is CTSD p.Pro89Leu (c.266C>T) pathogenic?

CTSD p.Pro89Leu (c.266C>T) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.273); Very rare (popmax 8.47e-05%, nfe).

How common is CTSD p.Pro89Leu (c.266C>T) in the general population?

CTSD p.Pro89Leu (c.266C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CTSD p.Pro89Leu (c.266C>T)?

AlphaMissense predicts likely benign (score 0.273) — an in-silico prediction, not a clinical call.

CTSD p.Pro89Leu

c.266C>T · rs1845850373 · VCV2507189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.273	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -13.35	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	24.0	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 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.84e-05% 1/1,461,158 alleles · very rare

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: CTSD
Protein: p.Pro89Leu
Coding: c.266C>T
MANE Select: NM_001909
dbSNP: rs1845850373
Type: single nucleotide variant
Location: chr11:1759602 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 89: a turn; the peptidase a1 domain

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

Similar variants

CTSD p.Pro89= Conflicting classifications of pathogenicity ★ same residue
CTSD c.228+1G>A Likely pathogenic ★★ same type
CTSD p.Glu82Ter Pathogenic/Likely pathogenic ★★ same type
CTSD c.828-3C>A Uncertain significance ★★ same type
CTSD c.*210C>G Uncertain significance ★★ same type
CTSD p.Ala10Ser Uncertain significance ★★ ⚠ same type
CTSD p.Ala116Thr Uncertain significance ★★ ⚠ same type
CTSD p.Ala18Pro 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/ctsd-p-pro89leu (accessed [today's date]).

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