UVRAG

Chr 11

UV radiation resistance associated

Also known as: DHTX, VPS38, p63

NCBI Gene: 7405 ENSG00000198382 UniProt: Q9P2Y5 OMIM: 602493

The UVRAG protein regulates membrane trafficking pathways including autophagy, endocytosis, and transport between cellular compartments like the Golgi and endoplasmic reticulum. Mutations cause autosomal recessive primary microcephaly-23 with seizures and cortical blindness, typically presenting in infancy. This gene is highly constrained against loss-of-function variants, indicating that complete loss of UVRAG function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and encodes a protein with a C2 domain. The protein activates the Beclin1-PI(3)KC3 complex, promoting autophagy and suppressing the proliferation and tumorigenicity of human colon cancer cells. Chromosomal aberrations involving this gene are associated with left-right axis malformation and mutations in this gene have been associated with colon cancer. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.29

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.989

Z-score 4.76

OE 0.14 (0.07–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.49Z-score

OE missense 0.78 (0.71–0.86)

289 obs / 369.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.29)

0≤0.351.4

Missense OE?0.78 (0.71–0.86)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 5 / 35.7Missense obs/exp: 289 / 369.3Syn Z: 0.61

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 85

804 rare PASS variants

Rare truncating (LoF)

1 in 880

59 rare PASS variants

Rare synonymous (reference)

1 in 93

346 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UVRAG. 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 110	1 in 1,000
South Asian	~43k	1 in 78	1 in 580
Remaining (unassigned)	~30k	1 in 69	1 in 320
European (Finnish)	~27k	1 in 460	1 in 2,100
Admixed American	~22k	1 in 75	1 in 380
African / African American	~21k	1 in 60	1 in 720
East Asian	~20k	1 in 65	1 in 690
Ashkenazi Jewish	~13k	1 in 270	1 in 1,600
Middle Eastern	~2,884	1 in 67	1 in 530

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 15 coding exons well covered in gnomAD exomes; exons 1, 6, 11 marginal. Genomes: all 15.? see exons ↓