PHIP

Chr 6

PHIP subunit of CUL4-Ring ligase complex

Also known as: BRWD2, CHUJANS, DCAF14, DIDOD, RepID, WDR11, ndrp

NCBI Gene: 55023 ENSG00000146247 UniProt: Q8WWQ0

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.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that binds to the insulin receptor substrate 1 protein and regulates glucose transporter translocation in skeletal muscle cells. The encoded protein may also regulate growth and survival of pancreatic beta cells. Elevated copy number of this gene may be associated with melanoma severity and the encoded protein may promote melanoma metastasis in human patients. [provided by RefSeq, Oct 2016]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— PHIP

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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

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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

92 unique Pathogenic / Likely Pathogenic· 407 VUS of 895 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 8.93

OE 0.06 (0.03–0.11)

Highly constrained

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

Missense Constraint?

5.14Z-score

OE missense 0.53 (0.49–0.57)

508 obs / 954.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.11)

0≤0.351.4

Missense OE?0.53 (0.49–0.57)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

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

This gene — mechanism propensity

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 · 82% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFA genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.1

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

References

1.PMID 29209020 ↗

ClinVar Variant Classifications

895 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40

Likely Pathogenic52

VUS407

Likely Benign317

Benign26

Conflicting20

Pathogenic

Likely Pathogenic

407

VUS

317

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	40	0	0	0	40
Likely Pathogenic	35	14	3	0	52
VUS	12	355	33	7	407
Likely Benign	0	26	142	149	317
Benign	0	12	9	5	26
Conflicting	—				20
Total	87	407	187	161	862

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

View in ClinVar →

4 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap PHIP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →