ISCA1

Chr 9

iron-sulfur cluster assembly 1

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

NCBI Gene: 81689ENSG00000135070UniProt: Q9BUE6

ISCA1 encodes a mitochondrial protein that functions in the maturation of 4Fe-4S iron-sulfur clusters, which are essential for electron transfer reactions in cellular metabolism. Mutations cause multiple mitochondrial dysfunctions syndrome 5, an autosomal recessive disorder affecting multiple organ systems due to impaired mitochondrial function. The gene has relatively low constraint scores (pLI 0.17, LOEUF 0.99), suggesting tolerance to loss-of-function variants in the general population.

GeneReviewsResearchSummary from RefSeq, OMIM, UniProt
DNmechanismLOEUF 0.99
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 unique Pathogenic / Likely Pathogenic· 19 VUS of 71 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — ISCA1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
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
0.99LOEUF
pLI 0.171
Z-score 1.59
OE 0.32 (0.13–0.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.78Z-score
OE missense 0.73 (0.57–0.93)
47 obs / 64.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.32 (0.13–0.99)
0≤0.351.4
Missense OE0.73 (0.57–0.93)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 2 / 6.3Missense obs/exp: 47 / 64.7Syn Z: 0.46
DN
0.80top 10%
GOF
0.4875th %ile
LOF
0.4233th %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

71 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.

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 5 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
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