GCM2

Chr 6ADAR

glial cells missing transcription factor 2

Also known as: FIH2, GCMB, HRPT4, hGCMb

NCBI Gene: 9247ENSG00000124827UniProt: O75603OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismAD/ARLOEUF 0.802 OMIM phenotypes
Clinical Summary— GCM2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
4 unique Pathogenic / Likely Pathogenic· 76 VUS of 100 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
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 OE0.44 (0.26–0.80)
0≤0.351.4
Missense OE0.89 (0.80–0.98)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 8 / 18.1Missense obs/exp: 246 / 277.7Syn Z: 0.34
DN
0.5967th %ile
GOF
0.3391th %ile
LOF
0.51top 25%

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

DN1 literature citation
GOF1 literature citation

Literature Evidence

DNMost cases of autosomal dominant isolated hypoparathyroidism are caused by gain-of-function mutations in CASR or GNA11 or dominant negative mutations in GCM2 or PTH.PMID:30137364
GOFMost cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH.PMID:24823460

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

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic3
VUS76
Likely Benign19
1
Pathogenic
3
Likely Pathogenic
76
VUS
19
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
3
0
0
0
3
VUS
1
71
3
1
76
Likely Benign
0
1
2
16
19
Benign
0
0
0
0
0
Total47261799

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

View in ClinVar →

Protein Context — Lollipop Plot

GCM2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients