ISCA2

Chr 14AR

iron-sulfur cluster assembly 2

Also known as: HBLD1, ISA2, MMDS4, c14_5557

NCBI Gene: 122961ENSG00000165898UniProt: Q86U28

The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 4MIM #616370
AR
116
ClinVar variants
18
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ISCA2
🧬
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
18 Pathogenic / Likely Pathogenic· 53 VUS of 116 total submissions

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.
1.91LOEUF
pLI 0.000
Z-score -1.01
OE 1.41 (0.84–1.91)
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.
0.38Z-score
OE missense 0.88 (0.72–1.07)
71 obs / 80.7 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.1.41 (0.84–1.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.72–1.07)
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: 10 / 7.1Missense obs/exp: 71 / 80.7Syn Z: -1.12

ClinVar Variant Classifications

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic7
VUS53
Likely Benign36
Benign4
Conflicting5
11
Pathogenic
7
Likely Pathogenic
53
VUS
36
Likely Benign
4
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
11
0
11
Likely Pathogenic
0
2
5
0
7
VUS
2
41
9
1
53
Likely Benign
0
1
17
18
36
Benign
0
0
4
0
4
Conflicting
—5
Total2444619116

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

View in ClinVar →

Protein Context — Lollipop Plot

ISCA2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Multiple mitochondrial dysfunctions syndrome 4

MIM #616370

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ISCA2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
Alazami AM et al.·Cell Rep
2015
Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.
Toldo I et al.·Metab Brain Dis
2018Review
Differential diagnosis of lipoic acid synthesis defects.
Tort F et al.·J Inherit Metab Dis
2016Review
Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study.
Li Y et al.·Front Endocrinol (Lausanne)
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
Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival.
Hartman TG et al.·Neurogenetics
2020Case report
Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.
Alaimo JT et al.·Hum Mutat
2018Case report
A novel ISCA2 variant responsible for an early-onset neurodegenerative mitochondrial disorder: a case report of multiple mitochondrial dysfunctions syndrome 4.
Eidi M et al.·BMC Neurol
2019Case report
Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.
Zhan F et al.·Metab Brain Dis
2022Review
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
A novel missense mutation in ISCA2 causes aberrant splicing and leads to multiple mitochondrial dysfunctions syndrome 4.
Al-Hassnan Z et al.·Front Psychiatry
2024🔓 Open Access
Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins.
Du J et al.·Free Radic Biol Med
2023
A Case of Multiple Mitochondrial Dysfunctions Syndrome 4 with Novel ISCA2 Variants, Mimicking Post-Infectious Encephalitis.
Chin H et al.·Child Neurol Open
2023🔓 Open Access
ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma.
Green YS et al.·Oncogene
2022🔓 Open Access
ISCA2 deficiency leads to heme synthesis defects and impaired erythroid differentiation in K562 cells by indirect ROS-mediated IRP1 activation.
Wang J et al.·Biochim Biophys Acta Mol Cell Res
2022
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