RALGPS1

Chr 9

Ral GEF with PH domain and SH3 binding motif 1

Also known as: RALGEF2, RALGPS1A

NCBI Gene: 9649 ENSG00000136828 UniProt: Q5JS13 OMIM: 614444

The protein functions as a guanine nucleotide exchange factor for the small GTPase RALA and is involved in cytoskeletal organization. Loss-of-function mutations in RALGPS1 cause autosomal dominant neurodevelopmental disorder, as the gene is highly intolerant to loss-of-function variation (pLI=1.0, LOEUF=0.127). The pathogenic mechanism involves haploinsufficiency affecting Ral protein signal transduction pathways critical for normal neuronal development.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Ral protein signal transduction. Predicted to be located in cytoplasm. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2025]

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

0.13

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 5.51

OE 0.03 (0.01–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.09Z-score

OE missense 0.51 (0.45–0.58)

163 obs / 318.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.13)

0≤0.351.4

Missense OE?0.51 (0.45–0.58)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 1 / 37.3Missense obs/exp: 163 / 318.2Syn Z: 0.99

Background carrier burden — how many people carry a rare variant somewhere in RALGPS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 97

712 rare PASS variants

Rare truncating (LoF)

1 in 2,600

78 rare PASS variants

Rare synonymous (reference)

1 in 120

318 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RALGPS1. 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 91	1 in 610
South Asian	~43k	1 in 75	1 in 1,800
Remaining (unassigned)	~30k	1 in 110	1 in 3,000
European (Finnish)	~27k	1 in 280	≈ 1 in 8,600
Admixed American	~22k	1 in 120	1 in 660
African / African American	~21k	1 in 120	1 in 920
East Asian	~20k	1 in 94	1 in 1,100
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 99	none seen

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 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓