MTNR1A

Chr 4

melatonin receptor 1A

Also known as: MEL-1A-R, MT1

NCBI Gene: 4543 ENSG00000168412 UniProt: P48039 OMIM: 600665

This protein is a high-affinity G-protein coupled receptor for melatonin that mediates circadian rhythm and reproductive functions, primarily localized to the hypothalamic suprachiasmatic nucleus and pituitary. Mutations cause autosomal recessive nonsyndromic intellectual disability and may be associated with sleep disorders given the gene's role in melatonin signaling. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with recessive inheritance requiring biallelic mutations for disease manifestation.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.77

Clinical Summary— MTNR1A

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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

38 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MTNR1A

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?

1.77LOEUF

pLI 0.000

Z-score -0.22

OE 1.08 (0.65–1.77)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.87–1.10)

198 obs / 201.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.08 (0.65–1.77)

0≤0.351.4

Missense OE?0.98 (0.87–1.10)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 9 / 8.3Missense obs/exp: 198 / 201.7Syn Z: -0.01

This gene — mechanism propensity

0.81top 10%

GOF

0.85top 5%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS38

Likely Benign4

Benign6

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	38	0	0	38
Likely Benign	2	0	2	4
Benign	2	2	2	6
Total	42	2	4	48

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

View in ClinVar →

118 pathogenic / likely-pathogenic (of 155) ClinVar copy-number / structural variants overlap MTNR1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →