FASTKD2

Chr 2AR

FAST kinase domains 2

Also known as: COXPD44, KIAA0971

NCBI Gene: 22868 ENSG00000118246 UniProt: Q9NYY8 OMIM: 612322

The protein is essential for assembly of the mitochondrial large ribosomal subunit and controls 16S mitochondrial ribosomal RNA abundance, which is required for intra-mitochondrial translation. Mutations cause combined oxidative phosphorylation deficiency 44, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.75), reflecting its critical role in mitochondrial protein synthesis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is localized in the mitochondrial inner compartment and that may play a role in mitochondrial apoptosis. Nonsense mutations have been reported to result in cytochrome c oxidase deficiency. [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.751 OMIM phenotype

Clinical Summary— FASTKD2

🧬

Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 297 VUS of 532 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — FASTKD2

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?

0.75LOEUF

pLI 0.000

Z-score 2.60

OE 0.48 (0.32–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.67Z-score

OE missense 0.90 (0.82–0.99)

328 obs / 363.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.32–0.75)

0≤0.351.4

Missense OE?0.90 (0.82–0.99)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 14 / 29.2Missense obs/exp: 328 / 363.7Syn Z: -0.97

This gene — mechanism propensity

0.6647th %ile

GOF

0.6735th %ile

LOF

0.2582th %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

532 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic19

VUS297

Likely Benign128

Benign32

Conflicting27

Pathogenic

Likely Pathogenic

297

VUS

128

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	1	0	0	14
Likely Pathogenic	17	2	0	0	19
VUS	1	190	101	5	297
Likely Benign	0	17	58	53	128
Benign	0	1	30	1	32
Conflicting	—				27
Total	31	211	189	59	517

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap FASTKD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →