ALX1

Chr 12AR

ALX homeobox 1

Also known as: CART1, FND3, HEL23

NCBI Gene: 8092 ENSG00000180318 UniProt: Q15699 OMIM: 601527

The ALX1 protein is a sequence-specific DNA-binding transcription factor that regulates genes involved in craniofacial development and forebrain mesenchyme survival during early development. Mutations cause frontonasal dysplasia 3, a craniofacial malformation syndrome that follows autosomal recessive inheritance. This gene shows some constraint against loss-of-function variants (LOEUF 0.607), consistent with its essential role in early craniofacial development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Frontonasal dysplasia 3MIM #613456

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome · AR · 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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.176

Z-score 2.64

OE 0.27 (0.13–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.87–1.11)

183 obs / 186.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.13–0.61)

0≤0.351.4

Missense OE?0.98 (0.87–1.11)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 4 / 15.1Missense obs/exp: 183 / 186.7Syn Z: -0.25

Background carrier burden — how many people carry a rare variant somewhere in ALX1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

451 rare PASS variants

Rare truncating (LoF)

1 in 9,200

34 rare PASS variants

Rare synonymous (reference)

1 in 210

158 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALX1. 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 380	1 in 9,100
South Asian	~43k	1 in 170	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 30,000
European (Finnish)	~27k	1 in 880	none seen
Admixed American	~22k	1 in 140	≈ 1 in 22,000
African / African American	~21k	1 in 120	≈ 1 in 10,000
East Asian	~20k	1 in 160	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 840	none seen
Middle Eastern	~2,884	1 in 560	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.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓