DAP3

Chr 1AR

death associated protein 3

Also known as: DAP-3, MRP-S29, MRPS29, PRLTS7, S29mt, bMRP-10, mS29

NCBI Gene: 7818 ENSG00000132676 UniProt: P51398 OMIM: 602074

The protein functions as a component of the mitochondrial small ribosomal subunit and translates mitochondrial mRNAs, displaying GTPase activity and participating in interferon-gamma-induced cell death pathways. Mutations cause Perrault syndrome 7, an autosomal recessive disorder characterized by sensorineural hearing loss and ovarian dysgenesis in females. The gene is highly constrained against loss-of-function variants (pLI ~0, LOEUF 1.105), indicating that heterozygous loss-of-function is well-tolerated but homozygous loss causes disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that also participates in apoptotic pathways which are initiated by tumor necrosis factor-alpha, Fas ligand, and gamma interferon. This protein potentially binds ATP/GTP and might be a functional partner of the mitoribosomal protein S27. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Pseudogenes corresponding to this gene are found on chromosomes 1q and 2q. [provided by RefSeq, Dec 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.101 OMIM phenotype

Clinical Summary— DAP3

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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

8 unique Pathogenic / Likely Pathogenic· 76 VUS of 129 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DAP3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.17

OE 0.74 (0.50–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.31Z-score

OE missense 0.94 (0.84–1.06)

206 obs / 218.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.50–1.10)

0≤0.351.4

Missense OE?0.94 (0.84–1.06)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 17 / 23.1Missense obs/exp: 206 / 218.9Syn Z: 0.13

This gene — mechanism propensity

0.6260th %ile

GOF

0.3392th %ile

LOF

0.3551th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

129 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic5

VUS76

Likely Benign17

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	1	0	3
Likely Pathogenic	2	3	0	0	5
VUS	0	75	1	0	76
Likely Benign	0	11	1	5	17
Benign	0	5	0	1	6
Conflicting	—				1
Total	4	94	3	6	108

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap DAP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →