IMPACT

Chr 18

impact RWD domain protein

Also known as: RWDD5

NCBI Gene: 55364 ENSG00000154059 UniProt: Q9P2X3 OMIM: 615319

IMPACT encodes a translational regulator that maintains protein synthesis during cellular stress conditions by inhibiting the GCN2 kinase pathway and is required for proper neuronal differentiation and neurite outgrowth. Mutations cause autosomal recessive intellectual disability with seizures and spasticity, typically manifesting in early childhood. This gene is highly intolerant to loss-of-function variants, primarily affecting the central nervous system.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein sequestering activity. Predicted to be involved in several processes, including GCN2-mediated signaling; cellular response to amino acid starvation; and regulation of gene expression. Predicted to act upstream of or within negative regulation of protein phosphorylation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.12

LOEUF

Mechanism· predicted

📖

GeneReview available — IMPACT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 1.15

OE 0.72 (0.47–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.96 (0.85–1.10)

165 obs / 171.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.47–1.12)

0≤0.351.4

Missense OE?0.96 (0.85–1.10)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 14 / 19.5Missense obs/exp: 165 / 171.2Syn Z: -0.64

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

413 rare PASS variants

Rare truncating (LoF)

1 in 2,100

80 rare PASS variants

Rare synonymous (reference)

1 in 310

135 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IMPACT. 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 180	1 in 4,200
South Asian	~43k	1 in 120	1 in 1,200
Remaining (unassigned)	~30k	1 in 110	1 in 2,100
European (Finnish)	~27k	1 in 530	1 in 3,000
Admixed American	~22k	1 in 83	1 in 2,200
African / African American	~21k	1 in 160	1 in 710
East Asian	~20k	1 in 170	1 in 1,800
Ashkenazi Jewish	~13k	1 in 400	none seen
Middle Eastern	~2,883	1 in 110	1 in 570

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): 4 of 11 coding exons well covered in gnomAD exomes; exons 1, 3, 4, 5, 7 and 2 more marginal. Genomes: all 11.? see exons ↓