ARHGEF16

Chr 1

Rho guanine nucleotide exchange factor 16

Also known as: GEF16, NBR

NCBI Gene: 27237 ENSG00000130762 UniProt: Q5VV41 OMIM: 618871

The protein functions as a guanyl-nucleotide exchange factor that stimulates GDP-to-GTP exchange in RHOG GTPase and may activate RAC1 and CDC42, playing a role in chemotactic cell migration. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities. The gene is extremely intolerant to loss-of-function variants, indicating it is highly constrained and essential for normal development.

OMIM ResearchSummary from RefSeq, UniProt

Although the specific function of this protein is not known yet, it is thought to be involved in protein-protein and protein-lipid interactions. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.02

Clinical Summary— ARHGEF16

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

111 VUS of 145 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?

1.02LOEUF

pLI 0.000

Z-score 1.47

OE 0.72 (0.52–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.94 (0.86–1.02)

411 obs / 437.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.52–1.02)

0≤0.351.4

Missense OE?0.94 (0.86–1.02)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 24 / 33.1Missense obs/exp: 411 / 437.9Syn Z: -0.34

This gene — mechanism propensity

0.5967th %ile

GOF

0.6737th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

145 submitted variants in ClinVar

ClinVar

Classification Summary

VUS111

Likely Benign9

Benign3

111

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	111	0	0	111
Likely Benign	6	0	3	9
Benign	1	1	1	3
Total	118	1	4	123

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

View in ClinVar →

100 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap ARHGEF16 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →