DPEP1

Chr 16

dipeptidase 1

Also known as: MBD1, MDP, RDP

NCBI Gene: 1800 ENSG00000015413 UniProt: P16444 OMIM: 179780

The protein is a zinc-dependent dipeptidase that hydrolyzes dipeptides including the conversion of leukotriene D4 to leukotriene E4, processes cystinyl-bis-glycine during glutathione degradation, and exhibits beta-lactamase activity against imipenem. Mutations in DPEP1 cause autosomal recessive dipeptidase 1 deficiency, which presents with renal dysfunction and metabolic abnormalities. The gene shows low constraint against loss-of-function variants, consistent with recessive inheritance requiring biallelic mutations for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a kidney membrane enzyme involved in the metabolism of glutathione and other similar proteins by dipeptide hydrolysis. The encoded protein is known to regulate leukotriene activity by catalyzing the conversion of leukotriene D4 to leukotriene E4. This protein uses zinc as a cofactor and acts as a disulfide-linked homodimer. [provided by RefSeq, Dec 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.31

Clinical Summary— DPEP1

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

50 VUS of 55 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.54

OE 0.86 (0.58–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.12Z-score

OE missense 1.19 (1.09–1.31)

318 obs / 266.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.58–1.31)

0≤0.351.4

Missense OE?1.19 (1.09–1.31)

0≤0.61.4

Synonymous OE?1.34

0≤1.21.6

LoF obs/exp: 16 / 18.5Missense obs/exp: 318 / 266.8Syn Z: -2.90

This gene — mechanism propensity

0.7230th %ile

GOF

0.72top 25%

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

VUS50

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	50	50
Likely Benign	1	1
Benign	0	0
Total	51	51

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 84) ClinVar copy-number / structural variants overlap DPEP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →