PHIP

Chr 6AD

pleckstrin homology domain interacting protein

This gene encodes a protein that regulates insulin and insulin-like growth factor signaling pathways, stimulates cell proliferation through cyclin transcription regulation, and has anti-apoptotic activity through AKT1 phosphorylation. Mutations cause Chung-Jansen syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.113), indicating intolerance to protein-disrupting mutations.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.111 OMIM phenotype
Clinical SummaryPHIP
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Gene-Disease Validity (ClinGen)
PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.11LOEUF
pLI 1.000
Z-score 8.93
OE 0.06 (0.030.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
5.14Z-score
OE missense 0.53 (0.490.57)
508 obs / 954.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.06 (0.030.11)
00.351.4
Missense OE0.53 (0.490.57)
00.61.4
Synonymous OE0.98
01.21.6
LoF obs/exp: 6 / 104.6Missense obs/exp: 508 / 954.9Syn Z: 0.30
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePHIP-related developmental delay, intellectual disability, obesity, and dysmorphic featuresLOFAD
DN
0.2698th %ile
GOF
0.3193th %ile
LOF
0.81top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.11

Literature Evidence

LOFA genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.PMID:29209020

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

PHIP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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