ARHGEF28

Chr 5

Rho guanine nucleotide exchange factor 28

Also known as: RGNEF, RIP2, p190RHOGEF

NCBI Gene: 64283ENSG00000214944UniProt: Q8N1W1

This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

476
ClinVar variants
5
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ARHGEF28
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis · SDLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 269 VUS of 476 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.000
Z-score 3.83
OE 0.55 (0.44–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.73Z-score
OE missense 0.93 (0.88–0.99)
823 obs / 884.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.44–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.88–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 47 / 85.1Missense obs/exp: 823 / 884.4Syn Z: 1.61

ClinVar Variant Classifications

476 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
VUS269
Likely Benign95
Benign106
Conflicting1
5
Pathogenic
269
VUS
95
Likely Benign
106
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
0
0
0
VUS
2
256
10
1
269
Likely Benign
0
35
13
47
95
Benign
0
14
77
15
106
Conflicting
—1
Total230510563476

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

View in ClinVar →

Protein Context — Lollipop Plot

ARHGEF28 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis.
Song Y et al.·Neurobiol Aging
2020
Discovery of biomarkers in the psoriasis through machine learning and dynamic immune infiltration in three types of skin lesions.
Zhou X et al.·Front Immunol
2024
Rare-variant association analysis reveals known and new age-related hearing loss genes.
Cornejo-Sanchez DM et al.·Eur J Hum Genet
2023
Genetic associations with dementia-related proteinopathy: Application of item response theory.
Katsumata Y et al.·Alzheimers Dement
2024
Expanding the spectrum of genes responsible for hereditary motor neuropathies.
Previtali SC et al.·J Neurol Neurosurg Psychiatry
2019
ARHGEF28 gene exon 6/intron 6 junction mutations in Chinese amyotrophic lateral sclerosis cohort.
Ma Y et al.·Amyotroph Lateral Scler Frontotemporal Degener
2014Cohort
Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration.
Zaritsky A et al.·J Cell Biol
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools