ARL4D

Chr 17

ARF like GTPase 4D

Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Recruits CYTH1, CYTH2, CYTH3 and CYTH4 to the plasma membrane in GDP-bound form

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

2.0

Missense Z

1.20

LOEUF

Clinical Summary— ARL4D

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

Some data sources returned errors (2)

ncbi: TypeError: fetch failed

pubmed: TypeError: fetch failed

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

1.20LOEUF

pLI 0.038

Z-score 1.26

OE 0.46 (0.21–1.20)

Tolerant

Highly tolerant — LoF variants common in population

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.

1.98Z-score

OE missense 0.51 (0.42–0.63)

67 obs / 130.9 exp

Tolerant

Mild missense constraint

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.0.46 (0.21–1.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.51 (0.42–0.63)

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.0.78

0≤1.21.6

LoF obs/exp: 3 / 6.5Missense obs/exp: 67 / 130.9Syn Z: 1.35

0.6939th %ile

GOF

0.6736th %ile

LOF

0.3454th %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.