NFU1

Chr 2

NFU1 iron-sulfur cluster scaffold

NCBI Gene: 27247ENSG00000169599UniProt: Q9UMS0

Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins

Primary Disease Associations & Inheritance

UniProtMultiple mitochondrial dysfunctions syndrome 1
UniProtSpastic paraplegia 93, autosomal recessive
224
ClinVar variants
29
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NFU1
🧬
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
29 Pathogenic / Likely Pathogenic· 84 VUS of 224 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.37Z-score
OE missense 0.91 (0.79–1.06)
123 obs / 135.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.73 (0.45–1.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.79–1.06)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 10 / 13.8Missense obs/exp: 123 / 135.1Syn Z: 0.60

ClinVar Variant Classifications

224 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic11
VUS84
Likely Benign68
Benign33
Conflicting10
18
Pathogenic
11
Likely Pathogenic
84
VUS
68
Likely Benign
33
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
6
10
0
18
Likely Pathogenic
3
4
4
0
11
VUS
2
57
22
3
84
Likely Benign
0
0
47
21
68
Benign
0
3
29
1
33
Conflicting
—10
Total77011225224

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

View in ClinVar →

Protein Context — Lollipop Plot

NFU1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NFU1-related multiple mitochondrial dysfunctions syndrome

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
frameshift variantmissense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.
Niihori M et al.·J Exp Med
2024
Lipoic acid biosynthesis defects.
Mayr JA et al.·J Inherit Metab Dis
2014Review
Phenotypic continuum of NFU1-related disorders.
Kaiyrzhanov R et al.·Ann Clin Transl Neurol
2022
Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.
Stark JC et al.·Genome Med
2025Cohort
Differential diagnosis of lipoic acid synthesis defects.
Tort F et al.·J Inherit Metab Dis
2016Review
Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension.
Niihori M et al.·Am J Respir Cell Mol Biol
2020
Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease.
Ferrer-Cortès X et al.·J Inherit Metab Dis
2013Cohort
Yeast models of mutations in NFU1 gene for biochemical characterization and drug screening.
Liu S et al.·Biochem Biophys Res Commun
2025Functional
Assembly of the [4Fe-4S] cluster of NFU1 requires the coordinated donation of two [2Fe-2S] clusters from the scaffold proteins, ISCU2 and ISCA1.
Jain A et al.·Hum Mol Genet
2020
Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.
Zhan F et al.·Metab Brain Dis
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools