AP1G1

Chr 16ADAR

adaptor related protein complex 1 subunit gamma 1

Also known as: ADTG, CLAPG1, USRISD

NCBI Gene: 164 ENSG00000166747 UniProt: O43747

Adaptins are important components of clathrin-coated vesicles transporting ligand-receptor complexes from the plasma membrane or from the trans-Golgi network to lysosomes. The adaptin family of proteins is composed of four classes of molecules named alpha, beta-, beta prime- and gamma- adaptins. Adaptins, together with medium and small subunits, form a heterotetrameric complex called an adaptor, whose role is to promote the formation of clathrin-coated pits and vesicles. The protein encoded by this gene is a gamma-adaptin protein and it belongs to the adaptor complexes large subunits family. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Usmani-Riazuddin syndrome, autosomal dominantMIM #619467

Usmani-Riazuddin syndrome, autosomal recessiveMIM #619548

Active trials

Pathogenic / LP

220

ClinVar variants

Pubs (1 yr)

3.0

Missense Z

0.20

LOEUF· LoF intolerant

Clinical Summary— AP1G1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADStrong

Strong evidence — appropriate for clinical testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

52 Pathogenic / Likely Pathogenic· 127 VUS of 220 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.20LOEUF

pLI 1.000

Z-score 6.05

OE 0.10 (0.05–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

2.98Z-score

OE missense 0.61 (0.55–0.67)

277 obs / 456.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.10 (0.05–0.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.55–0.67)

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.1.03

0≤1.21.6

LoF obs/exp: 5 / 52.2Missense obs/exp: 277 / 456.4Syn Z: -0.30

0.4289th %ile

GOF

0.4480th %ile

LOF

0.61top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 21% of P/LP variants are LoF · LOEUF 0.20

Literature Evidence

LOFThe frameshift mutations caused a loss of AP1G1 protein expression, suggesting haploinsufficiency.PMID:34102099

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.