UBAC2

Chr 13

UBA domain containing 2

Also known as: PHGDHL1

NCBI Gene: 337867 ENSG00000134882 UniProt: Q8NBM4 OMIM: 621399

The UBAC2 protein restricts trafficking of FAF2 from the endoplasmic reticulum to lipid droplets and negatively regulates canonical Wnt signaling by promoting ubiquitin-mediated degradation of key Wnt pathway components including CTNNB1 and receptors FZD6 and LRP6. Mutations cause autosomal recessive intellectual disability with microcephaly, seizures, and spasticity. The gene shows tolerance to loss-of-function variants (LOEUF 0.696), suggesting the recessive inheritance pattern reflects the need for complete loss of function to produce disease.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable serine-type endopeptidase activity. Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of retrograde protein transport, ER to cytosol. Acts upstream of or within protein localization to endoplasmic reticulum. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.70

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.006

Z-score 2.53

OE 0.37 (0.21–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.57Z-score

OE missense 0.68 (0.58–0.78)

126 obs / 186.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.70)

0≤0.351.4

Missense OE?0.68 (0.58–0.78)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 7 / 18.9Missense obs/exp: 126 / 186.4Syn Z: 0.71

Background carrier burden — how many people carry a rare variant somewhere in UBAC2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

487 rare PASS variants

Rare truncating (LoF)

1 in 1,500

90 rare PASS variants

Rare synonymous (reference)

1 in 440

182 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UBAC2. 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 190	1 in 1,400
South Asian	~43k	1 in 120	1 in 1,100
Remaining (unassigned)	~30k	1 in 160	1 in 1,700
European (Finnish)	~27k	1 in 420	1 in 2,700
Admixed American	~22k	1 in 120	≈ 1 in 5,600
African / African American	~21k	1 in 150	1 in 3,600
East Asian	~20k	1 in 120	1 in 2,100
Ashkenazi Jewish	~13k	1 in 620	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 360	≈ 1 in 1,300

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.

Exome coverage (gnomAD): 7 of 9 coding exons well covered in gnomAD exomes; exons 1, 3 marginal. Genomes: all 9.? see exons ↓