PLEKHH3

Chr 17

pleckstrin homology, MyTH4 and FERM domain containing H3

NCBI Gene: 79990 ENSG00000068137 UniProt: Q7Z736

Located in extracellular space. [provided by Alliance of Genome Resources, Jul 2025]

Active trials

Pathogenic / LP

151

ClinVar variants

Pubs (1 yr)

1.7

Missense Z

0.73

LOEUF

Clinical Summary— PLEKHH3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 Pathogenic / Likely Pathogenic· 140 VUS of 151 total submissions

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.

0.73LOEUF

pLI 0.000

Z-score 2.77

OE 0.48 (0.33–0.73)

Tolerant

Typical tolerance to LoF variation

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.

1.69Z-score

OE missense 0.77 (0.71–0.85)

344 obs / 444.2 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.0.48 (0.33–0.73)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.71–0.85)

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.0.80

0≤1.21.6

LoF obs/exp: 16 / 33.2Missense obs/exp: 344 / 444.2Syn Z: 2.24

0.5181th %ile

GOF

0.6930th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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.