# NM_004593.3(TRA2B):c.49G>C (p.Ala17Pro)

https://sugi.bio/variant/tra2b-p-ala17pro

## Summary

**TRA2B p.Ala17Pro (c.49G>C)** is classified **Uncertain significance** in TRA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-20). AlphaMissense: likely benign (0.1008); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the TRA2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRA2B](https://sugi.bio/atlas/gene/TRA2B/) |
| Protein change (HGVS p.) | p.Ala17Pro |
| Coding change (HGVS c.) | c.49G>C |
| MANE Select transcript | [NM_004593](https://www.ncbi.nlm.nih.gov/nuccore/NM_004593) |
| Variant type | single nucleotide variant |
| Location | chr3:185926722-185926722 (GRCh38) |
| ClinVar | [VCV3460644](https://www.ncbi.nlm.nih.gov/clinvar/variation/3460644/) |

**All HGVS expressions:** `NC_000003.11:g.185644510C>G`, `NC_000003.12:g.185926722C>G`, `NG_029862.1:g.16415G>C`, `NM_001243879.2:c.-130-1096G>C`, `NM_004593.3:c.49G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1008)
- REVEL 0.208 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.181 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.42) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.024, GERP 2.26, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (185,925,518–185,937,860), spanning 12,342 bp. Chi-square p 0.00064. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.42**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.42**, donor gain **0.00**.
- Pangolin: Δ**0.28** (gain), gain 0.28 / loss 0.12. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,012 in the highest group · 4/1,614,052 alleles overall — very rare (popmax 0.00667%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TRA2B** population constraint: LOEUF 0.528, pLI 0.95587, missense-Z 4.2143. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **17** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 57.18, 18% of residues very-high.

**4 experimental structure(s)** (PDB): [2CQC](https://www.rcsb.org/structure/2CQC), [2KXN](https://www.rcsb.org/structure/2KXN), [2RRA](https://www.rcsb.org/structure/2RRA), [2RRB](https://www.rcsb.org/structure/2RRB).

## What this gene does {#gene-function}

*Describes the biological roles of TRA2B (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TRA2B's established molecular role includes RNA binding. p.Ala17Pro falls in the disordered region.


### Pathways affected {#pathways}

TRA2B participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Processing of Capped Intron-Containing Pre-mRNA](https://reactome.org/content/detail/R-HSA-72203) | other |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | other |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | other |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | other |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, mRNA binding, protein domain specific binding, pre-mRNA binding, identical protein binding.

**Biological process:** regulation of alternative mRNA splicing, via spliceosome, mRNA splicing, via spliceosome, regulation of RNA splicing, positive regulation of mRNA splicing, via spliceosome, cellular response to glucose stimulus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-20 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related TRA2B variant pages (same residue, condition, or type): [TRA2B p.Arg74His](/variant/tra2b-p-arg74his), [TRA2B p.Arg82His](/variant/tra2b-p-arg82his), [TRA2B p.Arg91Cys](/variant/tra2b-p-arg91cys), [TRA2B p.Asn8Thr](/variant/tra2b-p-asn8thr), [TRA2B p.Asp146Asn](/variant/tra2b-p-asp146asn), [TRA2B p.Asp257Glu](/variant/tra2b-p-asp257glu), [TRA2B p.His98Arg](/variant/tra2b-p-his98arg), [TRA2B p.Ser270Thr](/variant/tra2b-p-ser270thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3460644). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*