GJC2

Chr 1ARAD

gap junction protein gamma 2

Also known as: CX46.6, Cx47, GJA12, HLD2, LMPH1C, LMPHM3, PMLDAR, SPG44

NCBI Gene: 57165ENSG00000198835UniProt: Q5T442

This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Spastic paraplegia 44, autosomal recessiveMIM #613206
AR
Leukodystrophy, hypomyelinating, 2MIM #608804
AR
Lymphatic malformation 3MIM #613480
AD
467
ClinVar variants
110
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— GJC2
🧬
Gene-Disease Validity (ClinGen)
hypomyelinating leukodystrophy 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
110 Pathogenic / Likely Pathogenic· 245 VUS of 467 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.
1.23LOEUF
pLI 0.010
Z-score 1.17
OE 0.54 (0.26–1.23)
Tolerant

Highly tolerant — LoF variants common in population

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.
1.87Z-score
OE missense 0.67 (0.59–0.76)
173 obs / 257.5 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.0.54 (0.26–1.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.59–0.76)
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.0.94
0≤1.21.6
LoF obs/exp: 4 / 7.4Missense obs/exp: 173 / 257.5Syn Z: 0.52

ClinVar Variant Classifications

467 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63
Likely Pathogenic47
VUS245
Likely Benign81
Benign8
Conflicting23
63
Pathogenic
47
Likely Pathogenic
245
VUS
81
Likely Benign
8
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
7
41
0
63
Likely Pathogenic
23
11
13
0
47
VUS
6
210
24
5
245
Likely Benign
0
4
7
70
81
Benign
0
0
4
4
8
Conflicting
—23
Total442328979467

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

View in ClinVar →

Protein Context — Lollipop Plot

GJC2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GJC2-related lymphatic malformation

moderate
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

GJC2-related leukodystrophy, hypomyelinating

definitive
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spastic paraplegia 44, autosomal recessive

MIM #613206

Molecular basis of disorder known

Autosomal recessive

Leukodystrophy, hypomyelinating, 2

MIM #608804

Molecular basis of disorder known

Autosomal recessive

Lymphatic malformation 3

MIM #613480

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GJC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular dynamics simulation of GJC2 mutants reveal pathogenic mechanisms of PMLD1 and SPG44.
Gong D et al.·J Gen Physiol
2025Functional
Inherited white matter disorders: Hypomyelination (myelin disorders).
Perrier S et al.·Handb Clin Neurol
2024Review
A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants.
Kilic MA et al.·Pediatr Neurol
2024Review
Diseases of connexins expressed in myelinating glia.
Abrams CK·Neurosci Lett
2019Review
Identification of GJC2 gene mutations in Chinese patients with Pelizaeus-Merzbacher-like disease.
Ji T et al.·Minerva Pediatr (Torino)
2023Cohort
Hypomyelinating leukodystrophy: From molecular mechanisms to clinical advances.
Osaka H et al.·Brain Dev
2025Review
Late-onset phenotype associated with a homozygous GJC2 missense mutation in a Turkish family.
Kuipers DJS et al.·Parkinsonism Relat Disord
2019Case report
Hypomyelinating leukodystrophies in adults: Clinical and genetic features.
Di Bella D et al.·Eur J Neurol
2021
Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population.
Kaur N et al.·Am J Med Genet A
2025
GJC2 missense mutations cause human lymphedema.
Ferrell RE et al.·Am J Hum Genet
2010
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