IDH3A

Chr 15

isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha

Also known as: RP90

NCBI Gene: 3419 ENSG00000166411 UniProt: P50213

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. [provided by RefSeq, Jul 2008]

Research

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtRetinitis pigmentosa 90

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.55

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.157

Z-score 2.99

OE 0.26 (0.14–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.59Z-score

OE missense 0.51 (0.44–0.60)

115 obs / 223.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.55)

0≤0.351.4

Missense OE?0.51 (0.44–0.60)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 5 / 19.1Missense obs/exp: 115 / 223.8Syn Z: -0.22

Background carrier burden — how many people carry a rare variant somewhere in IDH3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

372 rare PASS variants

Rare truncating (LoF)

1 in 3,400

62 rare PASS variants

Rare synonymous (reference)

1 in 230

144 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IDH3A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 230	1 in 3,600
South Asian	~43k	1 in 250	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 160	1 in 3,300
European (Finnish)	~27k	1 in 170	1 in 2,800
Admixed American	~22k	1 in 220	none seen
African / African American	~21k	1 in 170	1 in 1,700
East Asian	~20k	1 in 460	≈ 1 in 5,900
Ashkenazi Jewish	~13k	1 in 420	1 in 620
Middle Eastern	~2,884	1 in 190	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 11 coding exons well covered in gnomAD exomes; exons 4, 7, 11 marginal. Genomes: all 11.? see exons ↓