ARGFX

Chr 3

arginine-fifty homeobox

NCBI Gene: 503582 ENSG00000186103 UniProt: A6NJG6 OMIM: 611164

ARGFX encodes a transcription factor that acts as an activator and contains a homeodomain for DNA binding. Mutations cause autosomal recessive Joubert syndrome, a ciliopathy characterized by cerebellar vermis hypoplasia, developmental delay, and brainstem abnormalities. The gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Homeobox genes encode DNA-binding proteins, many of which are thought to be involved in early embryonic development. Homeobox genes encode a DNA-binding domain of 60 to 63 amino acids referred to as the homeodomain. This gene is a member of the ARGFX homeobox gene family. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.85

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.85LOEUF

pLI 0.000

Z-score -0.18

OE 1.09 (0.55–1.85)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.96 (0.84–1.10)

152 obs / 157.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.09 (0.55–1.85)

0≤0.351.4

Missense OE?0.96 (0.84–1.10)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 5 / 4.6Missense obs/exp: 152 / 157.6Syn Z: -1.74

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

337 rare PASS variants

Rare truncating (LoF)

1 in 1,300

58 rare PASS variants

Rare synonymous (reference)

1 in 250

139 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARGFX. 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 180	1 in 1,500
South Asian	~43k	1 in 130	1 in 520
Remaining (unassigned)	~30k	1 in 130	1 in 1,300
European (Finnish)	~27k	1 in 390	≈ 1 in 27,000
Admixed American	~22k	1 in 100	1 in 750
African / African American	~21k	1 in 130	1 in 950
East Asian	~20k	1 in 83	1 in 1,300
Ashkenazi Jewish	~13k	1 in 410	none seen
Middle Eastern	~2,884	1 in 110	≈ 1 in 1,400

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 3 poorly covered. Genomes: 3 of 4 (exon 3 below).? see exons ↓