NADSYN1

Chr 11AR

NAD synthetase 1

Also known as: VCRL3

NCBI Gene: 55191 ENSG00000172890 UniProt: Q6IA69 OMIM: 608285

NAD synthetase catalyzes the final step in nicotinamide adenine dinucleotide (NAD) biosynthesis, converting deamido-NAD to NAD using ATP and glutamine. Mutations cause vertebral, cardiac, renal, and limb defects syndrome 3, a congenital malformation disorder with autosomal recessive inheritance. The gene shows tolerance to loss-of-function variants (low constraint), consistent with the recessive inheritance pattern observed clinically.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— NADSYN1

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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

15 unique Pathogenic / Likely Pathogenic· 106 VUS of 179 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NADSYN1

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?

0.94LOEUF

pLI 0.000

Z-score 1.89

OE 0.70 (0.53–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.71Z-score

OE missense 0.91 (0.83–0.98)

407 obs / 449.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.53–0.94)

0≤0.351.4

Missense OE?0.91 (0.83–0.98)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 32 / 45.8Missense obs/exp: 407 / 449.4Syn Z: -1.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNADSYN1-related congenital NAD deficiency disorderLOFAR

This gene — mechanism propensity

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

0.7230th %ile

GOF

0.5268th %ile

LOF

0.3162th %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

179 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic8

VUS106

Likely Benign11

Benign15

Conflicting5

Pathogenic

Likely Pathogenic

106

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	0	0	7
Likely Pathogenic	4	4	0	0	8
VUS	3	100	3	0	106
Likely Benign	0	4	2	5	11
Benign	0	3	6	6	15
Conflicting	—				5
Total	13	112	11	11	152

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap NADSYN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →