PHIP

Chr 6AD

PHIP subunit of CUL4-Ring ligase complex

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

NCBI Gene: 55023 ENSG00000146247 UniProt: Q8WWQ0 OMIM: 612870

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Chung-Jansen syndromeMIM #617991

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome · AD · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

132

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in PHIP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 91

1,492 rare PASS variants

Rare truncating (LoF)

1 in 2,100

136 rare PASS variants

Rare synonymous (reference)

1 in 63

805 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PHIP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,900
South Asian	~43k	1 in 54	1 in 3,800
Remaining (unassigned)	~30k	1 in 77	≈ 1 in 10,000
European (Finnish)	~27k	1 in 160	1 in 2,400
Admixed American	~22k	1 in 70	1 in 910
African / African American	~21k	1 in 59	1 in 1,900
East Asian	~20k	1 in 89	1 in 1,100
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 100	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.