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…

LOFmechanismARLOEUF 0.611 OMIM phenotype

Clinical Summary— ALX1

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Gene-Disease Validity (ClinGen)

frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 38 VUS of 69 total submissions

Explore recent and relevant literature in Research Assistant →

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveALX1-related frontonasal dysplasiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7228th %ile

GOF

0.3690th %ile

LOF

0.59top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

69 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS38

Likely Benign16

Benign9

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	1	0	3
Likely Pathogenic	1	0	0	0	1
VUS	0	38	0	0	38
Likely Benign	0	4	3	9	16
Benign	0	2	4	3	9
Conflicting	—				1
Total	3	44	8	12	68

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap ALX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →