FDX2

Chr 19AR

ferredoxin 2

Also known as: FDX1L, MEOAL

NCBI Gene: 112812 ENSG00000267673 UniProt: Q6P4F2 OMIM: 614585

This protein serves as an electron donor in the mitochondrial iron-sulfur cluster assembly complex, essential for iron-sulfur protein biogenesis and coenzyme Q biosynthesis. Autosomal recessive mutations cause mitochondrial myopathy with episodic presentation, optic atrophy, and reversible leukoencephalopathy. The gene shows low constraint against loss-of-function variants (pLI 0.0016, LOEUF 1.41), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ferredoxin family. The encoded protein contains a 2Fe-2S ferredoxin-type domain and is essential for heme A and Fe/S protein biosynthesis. Mutation in FDX1L gene is associated with mitochondrial muscle myopathy. [provided by RefSeq, Sep 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.411 OMIM phenotype

Clinical Summary— FDX2

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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

4 unique Pathogenic / Likely Pathogenic· 45 VUS of 156 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.41LOEUF

pLI 0.002

Z-score 0.81

OE 0.68 (0.35–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.53Z-score

OE missense 0.86 (0.72–1.02)

91 obs / 106.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.35–1.41)

0≤0.351.4

Missense OE?0.86 (0.72–1.02)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 5 / 7.4Missense obs/exp: 91 / 106.4Syn Z: -1.64

This gene — mechanism propensity

0.6259th %ile

GOF

0.6834th %ile

LOF

0.3746th %ile

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

GOFprediction above median

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

156 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic4

VUS45

Likely Benign80

Benign22

Conflicting3

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	0	0	0	0	0
Likely Pathogenic	2	2	0	0	4
VUS	4	35	6	0	45
Likely Benign	0	0	35	45	80
Benign	0	3	15	4	22
Conflicting	—				3
Total	6	40	56	49	154

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap FDX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →