ISCA2

Chr 14AR

iron-sulfur cluster assembly 2

Also known as: HBLD1, ISA2, MMDS4, c14_5557

NCBI Gene: 122961 ENSG00000165898 UniProt: Q86U28 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 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

5 unique Pathogenic / Likely Pathogenic· 51 VUS of 102 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ISCA2

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?

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 OE?1.41 (0.84–1.91)

0≤0.351.4

Missense OE?0.88 (0.72–1.07)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 10 / 7.1Missense obs/exp: 71 / 80.7Syn Z: -1.12

This gene — mechanism propensity

0.6260th %ile

GOF

0.5563th %ile

LOF

0.4529th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF60% of P/LP variants are LoF

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

102 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS51

Likely Benign36

Benign4

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	2	2	0	0	4
VUS	2	42	6	1	51
Likely Benign	0	1	17	18	36
Benign	0	0	4	0	4
Conflicting	—				5
Total	5	45	27	19	101

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap ISCA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →