CTSD

Chr 11AR

cathepsin D

Also known as: CLN10, CPSD, HEL-S-130P

NCBI Gene: 1509 ENSG00000117984 UniProt: P07339 OMIM: 116840

The protein is a lysosomal enzyme that breaks down proteins and activates hormones and growth factors through pepsin-like proteolytic activity. Mutations cause neuronal ceroid lipofuscinosis-10, an autosomal recessive lysosomal storage disorder. The pathogenic mechanism involves dominant-negative effects where mutant protein disrupts normal lysosomal function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.801 OMIM phenotype

Clinical Summary— CTSD

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Gene-Disease Validity (ClinGen)

neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

55 unique Pathogenic / Likely Pathogenic· 282 VUS of 814 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CTSD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.001

Z-score 2.21

OE 0.44 (0.26–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.38Z-score

OE missense 0.76 (0.67–0.85)

190 obs / 251.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.26–0.80)

0≤0.351.4

Missense OE?0.76 (0.67–0.85)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 8 / 18.2Missense obs/exp: 190 / 251.6Syn Z: -0.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCTSD-related neuronal ceroid lipofuscinosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.5856th %ile

LOF

0.2971th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

814 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic18

VUS282

Likely Benign407

Benign27

Conflicting43

Pathogenic

Likely Pathogenic

282

VUS

407

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	32	2	3	0	37
Likely Pathogenic	16	2	0	0	18
VUS	4	228	46	4	282
Likely Benign	1	4	181	221	407
Benign	0	0	22	5	27
Conflicting	—				43
Total	53	236	252	230	814

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap CTSD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →