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…

DNmechanismAD/ARLOEUF 0.661 OMIM phenotype

Clinical Summary— PRRX1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 28 VUS of 53 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?

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPRRX1-related agnathia-otocephaly complexDNAD

limitedPRRX1-related agnathia-otocephaly complexOTHERAR

moderatePRRX1-related craniosynostosisOTHERAD

This gene — mechanism propensity

0.74top 25%

GOF

0.4282th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF50% of P/LP variants are LoF

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.

Literature Evidence

DNHowever, in cells in which PRRX1 with thep. Lys90Argfs*131 mutation was produced, the ability of theendogenously expressed wildtype PRRX1 to repress the humanTNC promoter was lost (Figure 2). This indicates that themutated protein functions in a dominant negative manner toprevent the normal actions 1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 22674740 ↗

ClinVar Variant Classifications

53 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS28

Likely Benign10

Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	0	1	0	0	1
VUS	1	26	1	0	28
Likely Benign	0	3	1	6	10
Benign	0	1	2	0	3
Total	4	33	4	6	47

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap PRRX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →