ISCA1

Chr 9AR

iron-sulfur cluster assembly 1

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

NCBI Gene: 81689 ENSG00000135070 UniProt: Q9BUE6 OMIM: 611006

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.991 OMIM phenotype

Clinical Summary— ISCA1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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GeneReview available — ISCA1

Authoritative clinical overview · Recommended first read

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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 OE?0.32 (0.13–0.99)

0≤0.351.4

Missense OE?0.73 (0.57–0.93)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 2 / 6.3Missense obs/exp: 47 / 64.7Syn Z: 0.46

This gene — mechanism propensity

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.