NFU1

Chr 2AR

NFU1 iron-sulfur cluster scaffold

Also known as: CGI-33, HIRIP, HIRIP5, MMDFS, MMDS1, NIFUC, Nfu, NifU

NCBI Gene: 27247 ENSG00000169599 UniProt: Q9UMS0 OMIM: 608100

The NFU1 protein localizes to mitochondria where it assembles and transfers 4Fe-4S clusters to target apoproteins including succinate dehydrogenase and lipoic acid synthase. Mutations cause multiple mitochondrial dysfunctions syndrome-1 and spastic paraplegia 93 through autosomal recessive inheritance. The pathogenic mechanism involves dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that is localized to mitochondria and plays a critical role in iron-sulfur cluster biogenesis. The encoded protein assembles and transfers 4Fe-4S clusters to target apoproteins including succinate dehydrogenase and lipoic acid synthase. Mutations in this gene are a cause of multiple mitochondrial dysfunctions syndrome-1, and pseudogenes of this gene are located on the short arms of chromosomes 1 and 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.232 OMIM phenotypes

Clinical Summary— NFU1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · 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

20 unique Pathogenic / Likely Pathogenic· 79 VUS of 216 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?

1.23LOEUF

pLI 0.000

Z-score 0.94

OE 0.73 (0.45–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.37Z-score

OE missense 0.91 (0.79–1.06)

123 obs / 135.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.45–1.23)

0≤0.351.4

Missense OE?0.91 (0.79–1.06)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 13.8Missense obs/exp: 123 / 135.1Syn Z: 0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNFU1-related multiple mitochondrial dysfunctions syndromeLOFAR

This gene — mechanism propensity

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

0.6744th %ile

GOF

0.5758th %ile

LOF

0.3261th %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

216 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic10

VUS79

Likely Benign69

Benign32

Conflicting10

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	1	6	3	0	10
Likely Pathogenic	4	4	2	0	10
VUS	2	59	15	3	79
Likely Benign	0	0	47	22	69
Benign	0	3	28	1	32
Conflicting	—				10
Total	7	72	95	26	210

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap NFU1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →