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…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 19MIM #618241

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.32

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in FOXRED1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 71

667 rare PASS variants

Rare truncating (LoF)

1 in 640

123 rare PASS variants

Rare synonymous (reference)

1 in 250

271 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOXRED1. 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 110	1 in 630
South Asian	~43k	1 in 74	1 in 780
Remaining (unassigned)	~30k	1 in 62	1 in 780
European (Finnish)	~27k	1 in 230	1 in 3,800
Admixed American	~22k	1 in 97	1 in 980
African / African American	~21k	1 in 67	1 in 1,100
East Asian	~20k	1 in 62	1 in 460
Ashkenazi Jewish	~13k	1 in 120	1 in 460
Middle Eastern	~2,884	1 in 90	≈ 1 in 2,900

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): 9 of 11 coding exons well covered in gnomAD exomes; exons 3, 10 marginal. Genomes: 9 of 11 (exons 8, 9 below).? see exons ↓