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…

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 4MIM #616370

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.91

LOEUF

Mechanism· predicted

📖

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 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

Background carrier burden — how many people carry a rare variant somewhere in ISCA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 480

201 rare PASS variants

Rare truncating (LoF)

1 in 3,100

47 rare PASS variants

Rare synonymous (reference)

1 in 400

116 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ISCA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 610	1 in 3,200
South Asian	~43k	1 in 580	1 in 8,300
Remaining (unassigned)	~30k	1 in 280	1 in 4,200
European (Finnish)	~27k	1 in 1,700	≈ 1 in 12,000
Admixed American	~22k	1 in 420	1 in 3,700
African / African American	~21k	1 in 280	1 in 2,900
East Asian	~20k	1 in 440	1 in 1,400
Ashkenazi Jewish	~13k	1 in 780	none seen
Middle Eastern	~2,884	1 in 470	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓