GGA2

Chr 16

golgi associated, gamma adaptin ear containing, ARF binding protein 2

Also known as: VEAR

NCBI Gene: 23062 ENSG00000103365 UniProt: Q9UJY4 OMIM: 606005

This gene encodes a coat protein that regulates trafficking of proteins between the trans-Golgi network and lysosomes by mediating clathrin recruitment and binding ubiquitinated cargo molecules. Mutations cause autosomal recessive spastic paraplegia with intellectual disability and seizures, typically presenting in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.749), suggesting some tolerance to haploinsufficiency.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.75

Clinical Summary— GGA2

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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

127 VUS of 179 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 2.71

OE 0.50 (0.34–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.15Z-score

OE missense 0.98 (0.89–1.07)

327 obs / 334.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.34–0.75)

0≤0.351.4

Missense OE?0.98 (0.89–1.07)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 17 / 34.0Missense obs/exp: 327 / 334.6Syn Z: -0.22

This gene — mechanism propensity

0.6453th %ile

GOF

0.6151th %ile

LOF

0.3068th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

179 submitted variants in ClinVar

ClinVar

Classification Summary

VUS127

Likely Benign13

Benign13

127

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	105	22	0	127
Likely Benign	4	6	3	13
Benign	0	13	0	13
Total	109	41	3	153

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap GGA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →