PRRX1

Chr 1ADAR

paired related homeobox 1

Also known as: AGOTC, PHOX1, PMX1, PRX-1, PRX1

NCBI Gene: 5396 ENSG00000116132 UniProt: P54821 OMIM: 167420

This gene encodes a homeobox transcription factor that regulates muscle creatine kinase and controls myofibroblast differentiation, playing essential roles in wound healing and mesodermal tissue development. Mutations cause agnathia-otocephaly complex, a severe congenital malformation involving absent or underdeveloped jaw and abnormal ear positioning. The condition shows both autosomal dominant and autosomal recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription co-activator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Agnathia-otocephaly complexMIM #202650

ADAR

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Agnathia-otocephaly complex; no ClinGen or GenCC tier

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.66

LOEUF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.243

Z-score 2.37

OE 0.26 (0.12–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.02Z-score

OE missense 0.76 (0.66–0.89)

114 obs / 149.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.12–0.66)

0≤0.351.4

Missense OE?0.76 (0.66–0.89)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 3 / 11.8Missense obs/exp: 114 / 149.1Syn Z: -1.61

Background carrier burden — how many people carry a rare variant somewhere in PRRX1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

337 rare PASS variants

Rare truncating (LoF)

1 in 12,000

24 rare PASS variants

Rare synonymous (reference)

1 in 320

175 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PRRX1. 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 250	1 in 20,000
South Asian	~43k	1 in 250	1 in 8,600
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 15,000
European (Finnish)	~27k	1 in 3,000	1 in 5,300
Admixed American	~22k	1 in 220	≈ 1 in 5,600
African / African American	~21k	1 in 290	≈ 1 in 6,400
East Asian	~20k	1 in 600	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,884	1 in 130	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 ↓