GJC2

Chr 1ARAD

gap junction protein gamma 2

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

NCBI Gene: 57165 ENSG00000198835 UniProt: Q5T442 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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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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 OE0.54 (0.26–1.23)

0≤0.351.4

Missense OE0.67 (0.59–0.76)

0≤0.61.4

Synonymous OE0.94

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

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, UPMID:15192806

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