CARNS1

Chr 11

carnosine synthase 1

Also known as: ATPGD1

NCBI Gene: 57571 ENSG00000172508 UniProt: A5YM72 OMIM: 613368

The CARNS1 protein catalyzes the synthesis of carnosine and homocarnosine, dipeptides found primarily in skeletal muscle and the central nervous system. Mutations in CARNS1 cause carnosinemia, an autosomal recessive disorder characterized by neurological manifestations including developmental delay, intellectual disability, and seizures. The gene is highly constrained against loss-of-function variants, suggesting that complete loss of protein function is poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

CARNS1 (EC 6.3.2.11), a member of the ATP-grasp family of ATPases, catalyzes the formation of carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyryl-L-histidine), which are found mainly in skeletal muscle and the central nervous system, respectively (Drozak et al., 2010 [PubMed 20097752]).[supplied by OMIM, Apr 2010]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.06

OE 0.54 (0.35–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.03Z-score

OE missense 0.87 (0.80–0.94)

397 obs / 458.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.35–0.86)

0≤0.351.4

Missense OE?0.87 (0.80–0.94)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 13 / 23.9Missense obs/exp: 397 / 458.9Syn Z: 1.52

Background carrier burden — how many people carry a rare variant somewhere in CARNS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 39

1,375 rare PASS variants

Rare truncating (LoF)

1 in 360

200 rare PASS variants

Rare synonymous (reference)

1 in 77

604 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CARNS1. 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 52	1 in 380
South Asian	~43k	1 in 32	1 in 300
Remaining (unassigned)	~30k	1 in 39	1 in 320
European (Finnish)	~27k	1 in 97	1 in 690
Admixed American	~22k	1 in 38	1 in 710
African / African American	~21k	1 in 30	1 in 450
East Asian	~20k	1 in 37	1 in 510
Ashkenazi Jewish	~13k	1 in 260	1 in 2,600
Middle Eastern	~2,884	1 in 30	1 in 450

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 9 coding exons well covered in gnomAD exomes; exons 3, 4, 8, 9 marginal. Genomes: all 9.? see exons ↓