GLIS3

Chr 9AR

GLIS family zinc finger 3

NCBI Gene: 169792ENSG00000107249UniProt: Q8NEA6

Acts both as a repressor and an activator of transcription. Binds to the consensus sequence 5'-GACCACCCAC-3' (By similarity)

Primary Disease Associations & Inheritance

Diabetes mellitus, neonatal, with congenital hypothyroidismMIM #610199
AR
684
ClinVar variants
66
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— GLIS3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 386 VUS of 684 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

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.
0.74LOEUF
pLI 0.000
Z-score 2.81
OE 0.50 (0.34–0.74)
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.
-3.14Z-score
OE missense 1.37 (1.29–1.46)
772 obs / 562.7 exp
Tolerant

Tolerant to missense variation

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.0.50 (0.34–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.37 (1.29–1.46)
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.1.38
0≤1.21.6
LoF obs/exp: 18 / 36.3Missense obs/exp: 772 / 562.7Syn Z: -4.73

ClinVar Variant Classifications

684 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic14
VUS386
Likely Benign136
Benign74
Conflicting22
52
Pathogenic
14
Likely Pathogenic
386
VUS
136
Likely Benign
74
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
49
0
52
Likely Pathogenic
5
0
9
0
14
VUS
2
313
61
10
386
Likely Benign
0
10
45
81
136
Benign
0
1
71
2
74
Conflicting
—22
Total832623593684

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

View in ClinVar →

Protein Context — Lollipop Plot

GLIS3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GLIS3-related diabetes mellitus neonatal with congenital hypothyroidism

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Diabetes mellitus, neonatal, with congenital hypothyroidism

MIM #610199

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GLIS3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.
Meulebrouck S et al.·Diabetologia
2024Meta-analysis
Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology.
Couper MR et al.·J Pediatr Gastroenterol Nutr
2023Review
The role of GLIS3 in thyroid disease as part of a multisystem disorder.
Dimitri P·Best Pract Res Clin Endocrinol Metab
2017Review
Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism.
Zhang RJ et al.·Mol Cell Endocrinol
2021
Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants.
Sun J et al.·PLoS One
2019
Glis3 as a Critical Regulator of Thyroid Primordium Specification.
Rurale G et al.·Thyroid
2020
A novel variant in GLIS3 is associated with osteoarthritis.
Casalone E et al.·Ann Rheum Dis
2018
Expanding the Clinical Spectrum Associated With GLIS3 Mutations.
Dimitri P et al.·J Clin Endocrinol Metab
2015
MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants.
Hasballa I et al.·Int J Mol Sci
2024Review
GLIS3, a novel prognostic indicator of gastric adenocarcinoma, contributes to the malignant biological behaviors of tumor cells via modulating TGF-β1/TGFβR1/Smad1/5 signaling pathway.
Zhang Y et al.·Cytokine
2023
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
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
Congenital Hypothyroidism

Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism with in Situ Thyroid

RECRUITING
NCT06728735IRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2021-03-17

External Resources

Links to major genomics databases and tools