GCM2

Chr 6ADAR

glial cells missing transcription factor 2

Also known as: FIH2, GCMB, HRPT4, hGCMb

NCBI Gene: 9247ENSG00000124827UniProt: O75603

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]

Primary Disease Associations & Inheritance

Hyperparathyroidism 4MIM #617343
AD
Hypoparathyroidism, familial isolated 2MIM #618883
ADAR
331
ClinVar variants
54
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GCM2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
54 Pathogenic / Likely Pathogenic· 175 VUS of 331 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.80LOEUF
pLI 0.001
Z-score 2.21
OE 0.44 (0.26–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.68Z-score
OE missense 0.89 (0.80–0.98)
246 obs / 277.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.44 (0.26–0.80)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.80–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 8 / 18.1Missense obs/exp: 246 / 277.7Syn Z: 0.34

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic16
VUS175
Likely Benign59
Benign33
Conflicting10
38
Pathogenic
16
Likely Pathogenic
175
VUS
59
Likely Benign
33
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
2
32
0
38
Likely Pathogenic
3
6
7
0
16
VUS
3
139
24
9
175
Likely Benign
0
10
9
40
59
Benign
0
3
27
3
33
Conflicting
—10
Total101609952331

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperparathyroidism 4

MIM #617343

Molecular basis of disorder known

Autosomal dominant

Hypoparathyroidism, familial isolated 2

MIM #618883

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — GCM2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo-Controlled Trial.
Wong RH et al.·J Bone Miner Res
2020
Familial Hyperparathyroidism.
Blau JE et al.·Front Endocrinol (Lausanne)
2021Review
GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.
Vincze S et al.·J Clin Endocrinol Metab
2022
Intratumor heterogeneity in human parathyroid tumors.
Verdelli C et al.·Histol Histopathol
2020Review
Heritable hyperparathyroidism: Genetic insights and clinical implications.
Grover A et al.·Best Pract Res Clin Endocrinol Metab
2025Review
Germline mutations of GCM2 cause a novel variant of hereditary primary hyperparathyroidism.
Iacobone M et al.·Updates Surg
2025
Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders.
Canaff L et al.·Eur J Endocrinol
2022
GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.
Szalat A et al.·Front Endocrinol (Lausanne)
2023Cohort
Recent Topics Around Multiple Endocrine Neoplasia Type 1.
Marx SJ·J Clin Endocrinol Metab
2018Review
Analysis of Activating GCM2 Sequence Variants in Sporadic Parathyroid Adenomas.
Riccardi A et al.·J Clin Endocrinol Metab
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools