TRA2B

Chr 3AD

transformer 2 beta homolog

Also known as: Htra2-beta, PPP1R156, RAMELN, SFRS10, SRFS10, TRA2-BETA, TRAN2B

The protein functions as a sequence-specific serine/arginine splicing factor that controls pre-mRNA splicing by either activating or suppressing exon inclusion, including regulation of the survival motor neuron SMN2 gene. Mutations cause autosomal dominant developmental delay with or without dysmorphic facies and autism. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismADLOEUF 0.251 OMIM phenotype
Clinical SummaryTRA2B
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Gene-Disease Validity (ClinGen)
syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.25LOEUF
pLI 0.993
Z-score 3.86
OE 0.05 (0.020.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.50Z-score
OE missense 0.30 (0.240.37)
60 obs / 198.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.05 (0.020.25)
00.351.4
Missense OE0.30 (0.240.37)
00.61.4
Synonymous OE0.99
01.21.6
LoF obs/exp: 1 / 19.3Missense obs/exp: 60 / 198.7Syn Z: 0.04
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateTRA2B-related neurodevelopmental syndromeOTHERAD
DN
0.3196th %ile
GOF
0.3292th %ile
LOF
0.88top 5%

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

LOFprediction above median · LOEUF 0.25
DN1 literature citation

Literature Evidence

DNCONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β proPMID:36549593

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

TRA2B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC