RIPK4

Chr 21AR

receptor interacting serine/threonine kinase 4

Also known as: ANKK2, ANKRD3, CHANDS, DIK, NKRD3, PKK, PPS2, RIP4

NCBI Gene: 54101 ENSG00000183421 UniProt: P57078 OMIM: 605706

RIPK4 encodes a serine/threonine protein kinase that phosphorylates plakophilin-1 to promote keratinocyte differentiation and cell adhesion, playing an essential role in embryonic skin development and adult skin homeostasis. Autosomal recessive mutations cause CHAND syndrome and Bartsocas-Papas type 1 popliteal pterygium syndrome, both severe developmental disorders affecting skin, limbs, and other organ systems. The gene is highly intolerant to loss-of-function variants (LOEUF 0.594), reflecting its critical developmental role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a serine/threonine protein kinase that interacts with protein kinase C-delta. The encoded protein can also activate NFkappaB and is required for keratinocyte differentiation. This kinase undergoes autophosphorylation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

CHAND syndromeMIM #214350

Popliteal pterygium syndrome, Bartsocas-Papas type 1MIM #263650

UniProtBartsocas-Papas syndrome

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists CHAND syndrome; Popliteal pterygium syndrome, Bartsocas-Papas type 1; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.004

Z-score 3.15

OE 0.34 (0.20–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.89Z-score

OE missense 0.77 (0.71–0.83)

409 obs / 531.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.20–0.59)

0≤0.351.4

Missense OE?0.77 (0.71–0.83)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 9 / 26.5Missense obs/exp: 409 / 531.6Syn Z: -1.31

Background carrier burden — how many people carry a rare variant somewhere in RIPK4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

1,033 rare PASS variants

Rare truncating (LoF)

1 in 2,100

95 rare PASS variants

Rare synonymous (reference)

1 in 45

549 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RIPK4. 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 53	1 in 2,300
South Asian	~43k	1 in 41	1 in 2,100
Remaining (unassigned)	~30k	1 in 43	1 in 1,900
European (Finnish)	~27k	1 in 140	1 in 1,500
Admixed American	~22k	1 in 47	1 in 740
African / African American	~21k	1 in 38	1 in 880
East Asian	~20k	1 in 51	1 in 940
Ashkenazi Jewish	~13k	1 in 430	none seen
Middle Eastern	~2,884	1 in 47	≈ 1 in 2,700

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 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓