ISCA2

Chr 14AR

iron-sulfur cluster assembly 2

Also known as: HBLD1, ISA2, MMDS4, c14_5557

NCBI Gene: 122961ENSG00000165898UniProt: Q86U28OMIM: 615317

This mitochondrial protein functions in the maturation of 4Fe-4S iron-sulfur clusters, working late in the iron-sulfur cluster assembly pathway. Mutations cause multiple mitochondrial dysfunctions syndrome 4, inherited in an autosomal recessive pattern. The gene shows relatively low constraint to loss-of-function variation.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 1.911 OMIM phenotype
Clinical Summary— ISCA2
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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
18 unique Pathogenic / Likely Pathogenic· 53 VUS of 117 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — ISCA2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
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
0.38Z-score
OE missense 0.88 (0.72–1.07)
71 obs / 80.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE1.41 (0.84–1.91)
0≤0.351.4
Missense OE0.88 (0.72–1.07)
0≤0.61.4
Synonymous OE1.24
0≤1.21.6
LoF obs/exp: 10 / 7.1Missense obs/exp: 71 / 80.7Syn Z: -1.12
DN
0.6260th %ile
GOF
0.5563th %ile
LOF
0.4529th %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

117 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
1
0
10
0
11
Likely Pathogenic
1
2
4
0
7
VUS
2
42
8
1
53
Likely Benign
0
1
17
18
36
Benign
0
0
4
0
4
Conflicting
—5
Total4454319116

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.

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
Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly
Hendricks AL et al.·Int J Mol Sci
2021Functional
ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins.
Suraci D et al.·J Mol Biol
2021
Structural Plasticity of NFU1 Upon Interaction with Binding Partners: Insights into the Mitochondrial [4Fe-4S] Cluster Pathway
Da Vela S et al.·J Mol Biol
2023
An original cuproptosis-related genes signature effectively influences the prognosis and immune status of head and neck squamous cell carcinoma
Zheng X et al.·Front Genet
2023
Multi-Omic Insight Into the Molecular Networks of Mitochondrial Dysfunction in the Pathogenesis of Primary Open-Angle Glaucoma
Chen LH et al.·Transl Vis Sci Technol
2025
Top 5 full-text resultsSearch PubTator3 ↗
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
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
Top 5 results · since 2015Search 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
2024Open 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
2023Open Access
ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma.
Green YS et al.·Oncogene
2022Open 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 ↗

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