FOXRED1

Chr 11AR

FAD dependent oxidoreductase domain containing 1

Also known as: FP634, H17, MC1DN19

NCBI Gene: 55572 ENSG00000110074 UniProt: Q96CU9 OMIM: 613622

FOXRED1 encodes a FAD-dependent oxidoreductase that serves as a chaperone protein required for the assembly of mitochondrial complex I (NADH dehydrogenase), particularly during mid-late assembly stages. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance, typically presenting in infancy or early childhood with neurological symptoms, developmental delays, and multi-organ involvement. The gene shows extremely low constraint against loss-of-function variants (pLI near zero), consistent with its recessive disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that contains a FAD-dependent oxidoreductase domain. The encoded protein is localized to the mitochondria and may function as a chaperone protein required for the function of mitochondrial complex I. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.321 OMIM phenotype

Clinical Summary— FOXRED1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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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

64 unique Pathogenic / Likely Pathogenic· 145 VUS of 545 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FOXRED1

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?

1.32LOEUF

pLI 0.000

Z-score 0.26

OE 0.95 (0.69–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.40Z-score

OE missense 1.07 (0.97–1.18)

291 obs / 272.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.95 (0.69–1.32)

0≤0.351.4

Missense OE?1.07 (0.97–1.18)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 25 / 26.4Missense obs/exp: 291 / 272.3Syn Z: -1.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFOXRED1-related mitochondrial complex I deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6649th %ile

GOF

0.5170th %ile

LOF

0.3841th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

545 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic31

VUS145

Likely Benign268

Benign15

Conflicting38

Pathogenic

Likely Pathogenic

145

VUS

268

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	1	1	0	33
Likely Pathogenic	25	6	0	0	31
VUS	1	125	16	3	145
Likely Benign	0	6	112	150	268
Benign	0	1	14	0	15
Conflicting	—				38
Total	57	139	143	153	530

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

View in ClinVar →

68 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap FOXRED1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →