PTH2R

Chr 2

parathyroid hormone 2 receptor

Also known as: PTHR2

NCBI Gene: 5746 ENSG00000144407 UniProt: P49190 OMIM: 601469

This G-protein coupled receptor specifically binds parathyroid hormone and activates adenylyl cyclase, with abundant expression in brain and pancreas where it may function in neurotransmission and pancreatic regulation. Mutations cause primary failure of tooth eruption, an autosomal recessive disorder characterized by failure of teeth to erupt despite normal tooth and root development. The gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the G-protein coupled receptor 2 family. This protein is a receptor for parathyroid hormone (PTH). This receptor is more selective in ligand recognition and has a more specific tissue distribution compared to parathyroid hormone receptor 1 (PTHR1). It is activated only by PTH and not by parathyroid hormone-like hormone (PTHLH) and is particularly abundant in brain and pancreas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.39

Clinical Summary— PTH2R

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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

1 unique Pathogenic / Likely Pathogenic· 100 VUS of 129 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.39LOEUF

pLI 0.000

Z-score -0.13

OE 1.03 (0.77–1.39)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.77Z-score

OE missense 1.13 (1.03–1.23)

333 obs / 295.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.03 (0.77–1.39)

0≤0.351.4

Missense OE?1.13 (1.03–1.23)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 30 / 29.2Missense obs/exp: 333 / 295.5Syn Z: 0.28

This gene — mechanism propensity

0.74top 25%

GOF

0.81top 10%

LOF

0.2968th %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

129 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS100

Likely Benign14

Benign4

Likely Pathogenic

100

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	0	100	0	0	100
Likely Benign	2	5	3	4	14
Benign	0	0	1	3	4
Total	2	106	4	7	119

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap PTH2R — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →