ISCA1

Chr 9AR

iron-sulfur cluster assembly 1

Also known as: HBLD2, ISA1, MMDS5, hIscA, hIscA1

NCBI Gene: 81689ENSG00000135070UniProt: Q9BUE6

ISCA1 is a mitochondrial protein involved in the biogenesis and assembly of iron-sulfur clusters, which play a role in electron-transfer reactions (Cozar-Castellano et al., 2004 [PubMed 15262227]).[supplied by OMIM, Mar 2008]

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 5MIM #617613
AR
70
ClinVar variants
27
Pathogenic / LP
0.17
pLI score
0
Active trials
Clinical Summary— ISCA1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 19 VUS of 70 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.
0.99LOEUF
pLI 0.171
Z-score 1.59
OE 0.32 (0.13–0.99)
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.
0.78Z-score
OE missense 0.73 (0.57–0.93)
47 obs / 64.7 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.0.32 (0.13–0.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.57–0.93)
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.0.88
0≤1.21.6
LoF obs/exp: 2 / 6.3Missense obs/exp: 47 / 64.7Syn Z: 0.46

ClinVar Variant Classifications

70 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic3
VUS19
Likely Benign20
Benign3
Conflicting1
24
Pathogenic
3
Likely Pathogenic
19
VUS
20
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
23
0
24
Likely Pathogenic
0
0
3
0
3
VUS
0
16
3
0
19
Likely Benign
0
0
11
9
20
Benign
0
0
2
1
3
Conflicting
—1
Total017421070

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

View in ClinVar →

Protein Context — Lollipop Plot

ISCA1 · 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 5

MIM #617613

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ISCA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive Analysis Reveals That ISCA1 Is Correlated with Ferroptosis-Related Genes Across Cancers and Is a Biomarker in Thyroid Carcinoma.
Xiong D et al.·Genes (Basel)
2024
A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes.
Sheng H et al.·Animal Model Exp Med
2023
Identification of ISCA1 as novel immunological and prognostic biomarker for bladder cancer.
Zhou R et al.·Front Immunol
2022
Expanding the phenotype of mitochondrial disease: Novel pathogenic variant in ISCA1 leading to instability of the iron-sulfur cluster in the protein.
Lebigot E et al.·Mitochondrion
2020Case report
Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.
Shukla A et al.·J Hum Genet
2017Case report
Novel rat model of multiple mitochondrial dysfunction syndromes (MMDS) complicated with cardiomyopathy.
Ling Y et al.·Animal Model Exp Med
2021Functional
ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.
Torraco A et al.·Hum Mol Genet
2018Case report
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
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
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