RABGAP1L

Chr 1

RAB GTPase activating protein 1 like

Also known as: HHL, TBC1D18

NCBI Gene: 9910 ENSG00000152061 UniProt: B7ZAP0 OMIM: 609238

RABGAP1L encodes a protein that activates GTPases and regulates protein localization within cellular compartments including the Golgi apparatus, cilia, and endosomes. Mutations cause Warburg micro syndrome, a rare autosomal recessive disorder characterized by congenital cataracts, microcephaly, intellectual disability, and hypogonadism. The gene is highly constrained against loss-of-function variants, indicating its critical importance for normal development.

OMIM ResearchSummary from RefSeq

Enables GTPase activator activity and small GTPase binding activity. Acts upstream of or within regulation of protein localization. Located in several cellular components, including Golgi apparatus; cilium; and early endosome. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.51

Clinical Summary— RABGAP1L

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

133 VUS of 177 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 4.25

OE 0.34 (0.23–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.12Z-score

OE missense 0.85 (0.78–0.92)

360 obs / 424.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.23–0.51)

0≤0.351.4

Missense OE?0.85 (0.78–0.92)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 16 / 47.7Missense obs/exp: 360 / 424.9Syn Z: 0.17

This gene — mechanism propensity

0.74top 25%

GOF

0.7127th %ile

LOF

0.2775th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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

177 submitted variants in ClinVar

ClinVar

Classification Summary

VUS133

Likely Benign2

Benign4

133

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	133	0	133
Likely Benign	1	1	2
Benign	2	2	4
Total	136	3	139

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap RABGAP1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →