ADM2

Chr 22

adrenomedullin 2

Also known as: AM2, dJ579N16.4

NCBI Gene: 79924 ENSG00000128165 UniProt: Q7Z4H4 OMIM: 608682

ADM2 encodes intermedin/ADM2, a peptide hormone that regulates gastrointestinal and cardiovascular functions through activation of cAMP-dependent pathways via CALCRL-RAMP receptor complexes. Mutations cause autosomal recessive familial hypocalciuric hypercalcemia type 3, characterized by elevated serum calcium levels with inappropriately normal or elevated parathyroid hormone. The gene is not highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of hormones that play a role in the regulation of cardiovascular homeostasis, prolactin release, anti-diuresis, anti-natriuresis, and regulation of food and water intake. The encoded protein is proteolytically processed to generate one or more biologically active peptides. [provided by RefSeq, Jul 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.48

Clinical Summary— ADM2

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

31 VUS of 37 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ADM2

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?

1.48LOEUF

pLI 0.020

Z-score 0.85

OE 0.59 (0.27–1.48)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.11Z-score

OE missense 0.96 (0.80–1.17)

74 obs / 76.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.27–1.48)

0≤0.351.4

Missense OE?0.96 (0.80–1.17)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 3 / 5.1Missense obs/exp: 74 / 76.7Syn Z: -0.75

This gene — mechanism propensity

0.7036th %ile

GOF

0.4579th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

Likely Benign4

Benign1

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	21	10	0	31
Likely Benign	3	1	0	4
Benign	0	0	1	1
Total	24	11	1	36

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

View in ClinVar →

146 pathogenic / likely-pathogenic (of 166) ClinVar copy-number / structural variants overlap ADM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →