IBA57

Chr 1AR

iron-sulfur cluster assembly factor IBA57

Also known as: C1orf69, MMDS3, SPG74

NCBI Gene: 200205ENSG00000181873UniProt: Q5T440OMIM: 615316

The protein functions in the late stages of mitochondrial iron-sulfur cluster assembly, specifically in the biosynthesis of 4Fe-4S proteins essential for mitochondrial respiratory chain complexes. Mutations cause autosomal recessive spastic paraplegia-74 and multiple mitochondrial dysfunctions syndrome-3 through impaired iron-sulfur cluster biogenesis, leading to mitochondrial respiratory chain dysfunction.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 0.962 OMIM phenotypes
Clinical Summary— IBA57
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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.
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ClinVar Variants
74 unique Pathogenic / Likely Pathogenic· 171 VUS of 387 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
0.96LOEUF
pLI 0.008
Z-score 1.67
OE 0.46 (0.24–0.96)
Tolerant

Typical tolerance to LoF variation

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

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.46 (0.24–0.96)
0≤0.351.4
Missense OE1.11 (1.00–1.25)
0≤0.61.4
Synonymous OE1.24
0≤1.21.6
LoF obs/exp: 5 / 11.0Missense obs/exp: 219 / 196.4Syn Z: -1.83
DN
0.6841th %ile
GOF
0.5366th %ile
LOF
0.3941th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

387 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
16
5
31
1
53
Likely Pathogenic
12
5
4
0
21
VUS
4
151
14
2
171
Likely Benign
0
5
20
86
111
Benign
0
2
5
1
8
Conflicting
—9
Total321687490373

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 3 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Multiple Mitochondrial Dysfunction Syndrome Caused by IBA57 Gene Mutation: A Case Report and Literature Review.
Xu J et al.·Mol Genet Genomic Med
2026Open AccessReview
Establishment of human induced pluripotent stem cell line, NIMHi020-A from fibroblasts of a patient with IBA57 variant (p.Tyr113Cys).
Chettiyappa MB et al.·Stem Cell Res
2025
The first report of a successful birth by preimplantation genetic testing for leukodystrophy induced by IBA57 gene.
Wang J et al.·Taiwan J Obstet Gynecol
2025
[Clinical characteristics and genetic analysis of two children with Multiple mitochondrial dysfunction syndrome due to variants of IBA57 gene].
Wu Q et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025
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
2024Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients