NMNAT1

Chr 1AR

nicotinamide nucleotide adenylyltransferase 1

Also known as: LCA9, NMNAT, PNAT1, SHILCA

NCBI Gene: 64802ENSG00000173614UniProt: Q9HAN9

This gene encodes an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD). The encoded enzyme is one of several nicotinamide nucleotide adenylyltransferases, and is specifically localized to the cell nucleus. Activity of this protein leads to the activation of a nuclear deacetylase that functions in the protection of damaged neurons. Mutations in this gene have been associated with Leber congenital amaurosis 9. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes 1, 3, 4, 14, and 15. [provided by RefSeq, Jul 2014]

Primary Disease Associations & Inheritance

Leber congenital amaurosis 9MIM #608553
AR
Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosisMIM #619260
AR
278
ClinVar variants
0
Pathogenic / LP
0.04
pLI score
0
Active trials
Clinical Summary— NMNAT1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
278 total variants — no pathogenic classifications of 278 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.88LOEUF
pLI 0.035
Z-score 1.85
OE 0.38 (0.19–0.88)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.63Z-score
OE missense 0.86 (0.74–0.99)
129 obs / 150.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.19–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.74–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 4 / 10.4Missense obs/exp: 129 / 150.6Syn Z: 0.64

ClinVar Variant Classifications

278 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

NMNAT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NMNAT1-related Leber congenital amaurosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leber congenital amaurosis 9

MIM #608553

Molecular basis of disorder known

Autosomal recessive

Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis

MIM #619260

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.
Georgiou M et al.·Prog Retin Eye Res
2024Review
Leber Congenital Amaurosis.
Tsang SH et al.·Adv Exp Med Biol
2018Review
Clinical course of a Japanese girl with Leber congenital amaurosis associated with a novel nonsense pathogenic variant in NMNAT1: a case report and mini review.
Kayazawa T et al.·Ophthalmic Genet
2022Review
Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.
Yi Z et al.·Eye (Lond)
2022
NMNAT1 and hereditary spastic paraplegia (HSP): expanding the phenotypic spectrum of NMNAT1 variants.
Sadr Z et al.·Neuromuscul Disord
2023
Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature.
Hedergott A et al.·Graefes Arch Clin Exp Ophthalmol
2015Review
Genetic and Clinical Profile of Retinopathies Due to Disease-Causing Variants in Leber Congenital Amaurosis (LCA)-Associated Genes in a Large German Cohort.
Zobor D et al.·Int J Mol Sci
2023Cohort
Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.
Dueñas Rey A et al.·Genome Med
2024Functional
Clinical Characterization, Natural History, and Detailed Phenotyping of NMNAT1-Associated Leber Congenital Amaurosis.
Lee YJ et al.·Am J Ophthalmol
2025Natural history
NMNAT1 variants cause cone and cone-rod dystrophy.
Nash BM et al.·Eur J Hum Genet
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools