IBA57

Chr 1

iron-sulfur cluster assembly factor IBA57

Also known as: C1orf69, MMDS3, SPG74

NCBI Gene: 200205ENSG00000181873UniProt: Q5T440

The protein encoded by this gene localizes to the mitochondrion and is part of the iron-sulfur cluster assembly pathway. The encoded protein functions late in the biosynthesis of mitochondrial 4Fe-4S proteins. Defects in this gene have been associated with autosomal recessive spastic paraplegia-74 and with multiple mitochondrial dysfunctions syndrome-3. Two transcript variants encoding different isoforms have been found for this gene. The smaller isoform is not likely to be localized to the mitochondrion since it lacks the amino-terminal transit peptide. [provided by RefSeq, Jul 2015]

Primary Disease Associations & Inheritance

UniProtMultiple mitochondrial dysfunctions syndrome 3
UniProtSpastic paraplegia 74, autosomal recessive
373
ClinVar variants
74
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— IBA57
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 171 VUS of 373 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.
0.96LOEUF
pLI 0.008
Z-score 1.67
OE 0.46 (0.24–0.96)
Tolerant

Typical tolerance to LoF variation

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.
-0.57Z-score
OE missense 1.11 (1.00–1.25)
219 obs / 196.4 exp
Tolerant

Tolerant to missense variation

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.0.46 (0.24–0.96)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.00–1.25)
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.1.24
0≤1.21.6
LoF obs/exp: 5 / 11.0Missense obs/exp: 219 / 196.4Syn Z: -1.83

ClinVar Variant Classifications

373 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic21
VUS171
Likely Benign111
Benign8
Conflicting9
53
Pathogenic
21
Likely Pathogenic
171
VUS
111
Likely Benign
8
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
5
40
1
53
Likely Pathogenic
11
5
5
0
21
VUS
4
151
14
2
171
Likely Benign
0
5
20
86
111
Benign
0
2
5
1
8
Conflicting
—9
Total221688490373

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

View in ClinVar →

Protein Context — Lollipop Plot

IBA57 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.
Zhan F et al.·Metab Brain Dis
2022Review
Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes.
Torraco A et al.·J Neurol
2017
Lipoic acid biosynthesis defects.
Mayr JA et al.·J Inherit Metab Dis
2014Review
The iron-sulfur cluster assembly (ISC) protein Iba57 executes a tetrahydrofolate-independent function in mitochondrial [4Fe-4S] protein maturation.
Mühlenhoff U et al.·J Biol Chem
2022
Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.
Wongkittichote P et al.·Mol Genet Metab
2023Case report
Multiple Mitochondrial Dysfunction Syndrome Caused by IBA57 Gene Mutation: A Case Report and Literature Review.
Xu J et al.·Mol Genet Genomic Med
2026Review
Differential diagnosis of lipoic acid synthesis defects.
Tort F et al.·J Inherit Metab Dis
2016Review
Clinical characteristics of a case of multiple mitochondrial dysfunction syndrome 3.
Xu H et al.·Mol Genet Genomic Med
2024
Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial iron-sulfur cluster assembly machinery.
Nasta V et al.·Sci Rep
2019
Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57.
Bargagna B et al.·Int J Mol Sci
2024
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