GJD4

Chr 10

gap junction protein delta 4

Also known as: CX40.1

NCBI Gene: 219770 ENSG00000177291 UniProt: Q96KN9 OMIM: 611922

GJD4 encodes connexin-40.1, a protein that forms gap junction channels allowing direct intercellular communication and diffusion of small molecules between neighboring cells. Mutations in GJD4 cause autosomal recessive erythrokeratoderma variabilis et progressiva, a rare skin disorder characterized by transient erythematous patches and progressive hyperkeratotic plaques. The gene shows tolerance to loss-of-function variants (pLI=0.015, LOEUF=1.93), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Connexins, such as GJD4, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.93

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.93LOEUF

pLI 0.015

Z-score -0.73

OE 1.73 (0.49–1.93)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.01Z-score

OE missense 1.19 (1.07–1.32)

266 obs / 223.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.73 (0.49–1.93)

0≤0.351.4

Missense OE?1.19 (1.07–1.32)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 2 / 1.2Missense obs/exp: 266 / 223.7Syn Z: -2.16

Background carrier burden — how many people carry a rare variant somewhere in GJD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 78

674 rare PASS variants

Rare truncating (LoF)

1 in 690

99 rare PASS variants

Rare synonymous (reference)

1 in 190

309 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GJD4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,400
South Asian	~43k	1 in 81	1 in 450
Remaining (unassigned)	~30k	1 in 69	1 in 410
European (Finnish)	~27k	1 in 270	1 in 3,100
Admixed American	~22k	1 in 110	1 in 790
African / African American	~21k	1 in 66	1 in 330
East Asian	~20k	1 in 69	1 in 1,400
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 100	≈ 1 in 1,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓