RTN4IP1

Chr 6AR

reticulon 4 interacting protein 1

Also known as: NIMP, OPA10, Yim1

NCBI Gene: 84816 ENSG00000130347 UniProt: Q8WWV3 OMIM: 610502

RTN4IP1 encodes a mitochondrial NAD(P)H oxidoreductase required for ubiquinone biosynthesis and COQ3 O-methyltransferase activity, and may regulate retinal ganglion cell neurite outgrowth. Biallelic mutations cause autosomal recessive optic atrophy 10 with or without ataxia, intellectual disability, and seizures. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that heterozygous loss-of-function mutations are likely pathogenic in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mitochondrial protein that interacts with reticulon 4, which is a potent inhibitor of regeneration following spinal cord injury. This interaction may be important for reticulon-induced inhibition of neurite growth. Mutations in this gene can cause optic atrophy 10, with or without ataxia, cognitive disability, and seizures. There is a pseudogene for this gene on chromosome 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Optic atrophy 10 with or without ataxia, impaired intellectual development and seizuresMIM #616732

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · optic atrophy 10 with or without ataxia, intellectual disability, and seizures · AR · ClinGen 2024

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

0.94

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.78

OE 0.58 (0.37–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.73Z-score

OE missense 0.86 (0.77–0.97)

192 obs / 222.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.37–0.94)

0≤0.351.4

Missense OE?0.86 (0.77–0.97)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 12 / 20.8Missense obs/exp: 192 / 222.6Syn Z: -0.61

Background carrier burden — how many people carry a rare variant somewhere in RTN4IP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

466 rare PASS variants

Rare truncating (LoF)

1 in 1,200

69 rare PASS variants

Rare synonymous (reference)

1 in 230

177 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RTN4IP1. 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 150	1 in 1,100
South Asian	~43k	1 in 180	1 in 720
Remaining (unassigned)	~30k	1 in 98	1 in 1,400
European (Finnish)	~27k	1 in 480	1 in 1,800
Admixed American	~22k	1 in 170	1 in 2,100
African / African American	~21k	1 in 130	1 in 1,000
East Asian	~20k	1 in 120	1 in 1,100
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 100	≈ 1 in 720

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 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓