RBM4

Chr 11

RNA binding motif protein 4

Also known as: LARK, RBM4A, ZCCHC21, ZCRB3A

NCBI Gene: 5936 ENSG00000173933 UniProt: Q9BWF3 OMIM: 602571

This RNA-binding protein regulates alternative splicing of pre-mRNA and controls translation initiation, playing key roles in muscle cell differentiation and cellular stress responses. Mutations cause autosomal dominant neurodevelopmental disorders with developmental delay, intellectual disability, and seizures. The gene is highly constrained against loss-of-function variants (pLI = 0.99), indicating that such mutations are likely to cause severe developmental phenotypes.

OMIM ResearchSummary from RefSeq, UniProt

Enables RNA binding activity and cyclin binding activity. Involved in several processes, including IRES-dependent translational initiation of linear mRNA; negative regulation of translation; and regulation of alternative mRNA splicing, via spliceosome. Located in cytoplasmic stress granule; nuclear speck; and nucleolus. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 0.990

Z-score 3.45

OE 0.00 (0.00–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.98Z-score

OE missense 0.65 (0.57–0.74)

161 obs / 248.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.22)

0≤0.351.4

Missense OE?0.65 (0.57–0.74)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 0 / 13.9Missense obs/exp: 161 / 248.7Syn Z: -0.41

Background carrier burden — how many people carry a rare variant somewhere in RBM4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

526 rare PASS variants

Rare truncating (LoF)

1 in 1,600

75 rare PASS variants

Rare synonymous (reference)

1 in 190

274 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RBM4. 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 210	1 in 3,100
South Asian	~43k	1 in 170	1 in 630
Remaining (unassigned)	~30k	1 in 100	1 in 4,900
European (Finnish)	~27k	1 in 350	1 in 2,500
Admixed American	~22k	1 in 120	≈ 1 in 5,700
African / African American	~21k	1 in 200	≈ 1 in 5,800
East Asian	~20k	1 in 200	1 in 1,000
Ashkenazi Jewish	~13k	1 in 230	none seen
Middle Eastern	~2,884	1 in 100	≈ 1 in 2,800

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 ↓