GCM2

Chr 6ADAR

GCM transcription factor 2

Also known as: FIH2, GCMB, HRPT4, hGCMb

NCBI Gene: 9247 ENSG00000124827 UniProt: O75603 OMIM: 603716

This transcription factor serves as a master regulator of parathyroid gland development and controls parathyroid hormone expression and secretion in response to calcium levels. Mutations cause familial isolated hypoparathyroidism and hyperparathyroidism, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene shows low constraint against loss-of-function variants (pLI 0.0009, LOEUF 0.796), suggesting tolerance to complete gene loss in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a homolog of the Drosophila glial cells missing gene, which is thought to act as a binary switch between neuronal and glial cell determination. The protein encoded by this gene contains a conserved N-terminal GCM motif that has DNA-binding activity. The protein is a transcription factor that acts as a master regulator of parathyroid development. It has been suggested that this transcription factor might mediate the effect of calcium on parathyroid hormone expression and secretion in parathyroid cells. Mutations in this gene are associated with hypoparathyroidism. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hyperparathyroidism 4MIM #617343

Hypoparathyroidism, familial isolated 2MIM #618883

ADAR

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Hyperparathyroidism 4; Hypoparathyroidism, familial isolated 2; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — GCM2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.001

Z-score 2.21

OE 0.44 (0.26–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.68Z-score

OE missense 0.89 (0.80–0.98)

246 obs / 277.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.26–0.80)

0≤0.351.4

Missense OE?0.89 (0.80–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 8 / 18.1Missense obs/exp: 246 / 277.7Syn Z: 0.34

Background carrier burden — how many people carry a rare variant somewhere in GCM2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 79

566 rare PASS variants

Rare truncating (LoF)

1 in 4,000

62 rare PASS variants

Rare synonymous (reference)

1 in 150

240 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GCM2. 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 120	1 in 6,000
South Asian	~43k	1 in 85	1 in 1,400
Remaining (unassigned)	~30k	1 in 60	≈ 1 in 7,500
European (Finnish)	~27k	1 in 240	≈ 1 in 8,800
Admixed American	~22k	1 in 74	≈ 1 in 4,500
African / African American	~21k	1 in 79	1 in 780
East Asian	~20k	1 in 130	1 in 1,700
Ashkenazi Jewish	~13k	1 in 730	none seen
Middle Eastern	~2,884	1 in 85	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.