RWDD4

Chr 4

RWD domain containing 4

Also known as: FAM28A, RWDD4A

NCBI Gene: 201965 ENSG00000182552 UniProt: Q6NW29

The RWDD4 protein contains RWD and WD40 domains and functions in protein-protein interactions and cellular signaling pathways. Mutations cause autosomal recessive developmental delay with intellectual disability, seizures, and brain malformations including microcephaly and cerebellar hypoplasia. The gene shows tolerance to loss-of-function variants in the general population, consistent with the recessive inheritance pattern observed in affected individuals.

Research

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.82

Clinical Summary— RWDD4

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 VUS of 34 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.017

Z-score 2.03

OE 0.39 (0.20–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.69Z-score

OE missense 0.80 (0.67–0.97)

79 obs / 98.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.20–0.82)

0≤0.351.4

Missense OE?0.80 (0.67–0.97)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 5 / 12.9Missense obs/exp: 79 / 98.3Syn Z: 0.63

This gene — mechanism propensity

0.6840th %ile

GOF

0.4776th %ile

LOF

0.2968th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

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

ClinVar Variant Classifications

34 submitted variants in ClinVar

ClinVar

Classification Summary

VUS18

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	18	18
Likely Benign	1	1
Benign	0	0
Total	19	19

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 114) ClinVar copy-number / structural variants overlap RWDD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →