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…

DNmechanismLOEUF 1.85

Clinical Summary— ARGFX

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

35 VUS of 41 total submissions

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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

This gene — mechanism propensity

0.74top 25%

GOF

0.5562th %ile

LOF

0.3842th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS35

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	35	35
Likely Benign	5	5
Benign	0	0
Total	40	40

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap ARGFX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →