GJC2

Chr 1ARAD

gap junction protein gamma 2

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

NCBI Gene: 57165 ENSG00000198835 OMIM: 608803

This gene encodes connexin-47, a gap junction protein that forms intercellular channels essential for central nervous system myelination and oligodendrocyte function. Mutations cause autosomal recessive hypomyelinating leukodystrophy type 2 (Pelizaeus-Merzbacher-like disease) and can also lead to autosomal dominant spastic paraplegia 44 or lymphatic malformations. Disease can result from multiple mechanisms including gain-of-function effects, with different variants potentially causing distinct phenotypes through different pathogenic mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 1.233 OMIM phenotypes

Clinical Summary— GJC2

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Gene-Disease Validity (ClinGen)

hypomyelinating leukodystrophy 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

77 unique Pathogenic / Likely Pathogenic· 241 VUS of 432 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.87Z-score

OE missense 0.67 (0.59–0.76)

173 obs / 257.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.26–1.23)

0≤0.351.4

Missense OE?0.67 (0.59–0.76)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 4 / 7.4Missense obs/exp: 173 / 257.5Syn Z: 0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGJC2-related lymphatic malformationOTHERAD

definitiveGJC2-related leukodystrophy, hypomyelinatingOTHERAR

This gene — mechanism propensity

0.78top 25%

GOF

0.87top 5%

LOF

0.2873th %ile

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

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFSome patients showed reduced nerve conduction velocities, which indicated the presence of a mild peripheral demyelinating motor neuropathy, predominantly of the lower limbs, consistent with GJA12 expression in sural and sciatic nerve tissue. Since Gjb1 and Gja12 are functionally redundant in mice, U1

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

References

1.PMID 15192806 ↗

ClinVar Variant Classifications

432 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic45

VUS241

Likely Benign82

Benign7

Conflicting23

Pathogenic

Likely Pathogenic

241

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	25	7	0	0	32
Likely Pathogenic	30	13	2	0	45
VUS	6	226	4	5	241
Likely Benign	0	4	7	71	82
Benign	0	0	4	3	7
Conflicting	—				23
Total	61	250	17	79	430

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap GJC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →