NADSYN1

Chr 11AR

NAD synthetase 1

Also known as: VCRL3

NCBI Gene: 55191ENSG00000172890UniProt: Q6IA69

Nicotinamide adenine dinucleotide (NAD) is a coenzyme in metabolic redox reactions, a precursor for several cell signaling molecules, and a substrate for protein posttranslational modifications. NAD synthetase (EC 6.3.5.1) catalyzes the final step in the biosynthesis of NAD from nicotinic acid adenine dinucleotide (NaAD).[supplied by OMIM, Apr 2004]

Primary Disease Associations & Inheritance

Vertebral, cardiac, renal, and limb defects syndrome 3MIM #618845
AR
160
ClinVar variants
19
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NADSYN1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 111 VUS of 160 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.
0.94LOEUF
pLI 0.000
Z-score 1.89
OE 0.70 (0.53–0.94)
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.
0.71Z-score
OE missense 0.91 (0.83–0.98)
407 obs / 449.4 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.0.70 (0.53–0.94)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–0.98)
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.1.09
0≤1.21.6
LoF obs/exp: 32 / 45.8Missense obs/exp: 407 / 449.4Syn Z: -1.01

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic7
VUS111
Likely Benign10
Benign15
Conflicting5
12
Pathogenic
7
Likely Pathogenic
111
VUS
10
Likely Benign
15
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
8
0
12
Likely Pathogenic
0
3
4
0
7
VUS
2
98
11
0
111
Likely Benign
0
4
2
4
10
Benign
0
3
6
6
15
Conflicting
—5
Total51093110160

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

View in ClinVar →

Protein Context — Lollipop Plot

NADSYN1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NADSYN1-related congenital NAD deficiency disorder

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Vertebral, cardiac, renal, and limb defects syndrome 3

MIM #618845

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NADSYN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
Szot JO et al.·J Clin Invest
2024
Clinical heterogeneity of NADSYN1-associated VCRL syndrome.
Aubert-Mucca M et al.·Clin Genet
2023Case report
The genetics of vitamin D.
Jiang X et al.·Bone
2019Review
Genetic variants of vitamin D metabolism-related DHCR7/NADSYN1 locus and CYP2R1 gene are associated with clinical features of Parkinson's disease.
Alaylıoğlu M et al.·Int J Neurosci
2022
Further description of two patients with biallelic variants in NADSYN1 in association with cardiac and vertebral anomalies.
Kortbawi H et al.·Am J Med Genet A
2022Case report
Adult patient diagnosed with NADSYN1 associated congenital NAD deficiency and analysis of NAD levels to be published in: European Journal of Medical Genetics.
Erbs E et al.·Eur J Med Genet
2023Case report
Host genetic polymorphisms involved in long-term symptoms of COVID-19.
Udomsinprasert W et al.·Emerg Microbes Infect
2023
Genetic variants in vitamin D metabolism-related genes are associated with vitamin D status and adiposity markers.
Becerra-Cervera A et al.·Nutr Res
2025
Whole-genome sequencing for the prenatal evaluation of fetal structural anomalies: a prospective multicenter study.
Gao Z et al.·Am J Obstet Gynecol
2026
Unveiling Genetic Variants Underlying Vitamin D Deficiency in Multiple Korean Cohorts by a Genome-Wide Association Study.
Kim YA et al.·Endocrinol Metab (Seoul)
2021Cohort
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