# NM_001292034.3(TAB2):c.119A>T (p.Asp40Val)

https://sugi.bio/variant/tab2-p-asp40val

## Summary

**TAB2 p.Asp40Val (c.119A>T)** is classified **Uncertain significance** in TAB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). AlphaMissense: likely pathogenic (0.7149); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1781462536 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the TAB2 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 | [TAB2](https://sugi.bio/atlas/gene/TAB2/) |
| Protein change (HGVS p.) | p.Asp40Val |
| Coding change (HGVS c.) | c.119A>T |
| MANE Select transcript | [NM_001292034](https://www.ncbi.nlm.nih.gov/nuccore/NM_001292034) |
| dbSNP | [rs1781462536](https://www.ncbi.nlm.nih.gov/snp/rs1781462536/) |
| Variant type | single nucleotide variant |
| Location | chr6:149378034-149378034 (GRCh38) |
| ClinVar | [VCV3173208](https://www.ncbi.nlm.nih.gov/clinvar/variation/3173208/) |

**All HGVS expressions:** `NC_000006.11:g.149699170A>T`, `NC_000006.12:g.149378034A>T`, `NG_021386.2:g.165111A>T`, `NM_001292034.3:c.119A>T`, `NM_001292035.3:c.23A>T`, `NM_001369506.1:c.119A>T`, `NM_015093.6:c.119A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7149)
- REVEL 0.66 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.769 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.177, GERP 1.77, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.8**. 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 0.83** across the covering region of the MANE Select transcript (149,378,032–149,397,759), spanning 19,727 bp. Chi-square p 7.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.10**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.00**.
- Pangolin: Δ**0.24** (gain), gain 0.24 / loss 0.14. 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 **0.00133%** (afr) · 1/74,930 in the highest group · 2/1,613,842 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,930 |
| European (non-Finnish) | 8.48e-05% | 1,179,871 |

*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}

**TAB2** population constraint: LOEUF 0.117, pLI 1, missense-Z 3.2248; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **congenital heart defects, multiple types, 2** — Definitive (AD)

## Protein context {#protein}

Residue **40** lies in the cue domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 53.24, 14% of residues very-high.

**6 experimental structure(s)** (PDB): [2DAE](https://www.rcsb.org/structure/2DAE), [2WWZ](https://www.rcsb.org/structure/2WWZ), [2WX0](https://www.rcsb.org/structure/2WX0), [2WX1](https://www.rcsb.org/structure/2WX1), [9AVT](https://www.rcsb.org/structure/9AVT), [9AVW](https://www.rcsb.org/structure/9AVW).

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

*Describes the biological roles of TAB2 (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:** TAB2's established molecular role includes zinc ion binding. p.Asp40Val falls in the cue domain. In Reactome, TAB2 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** TAB2 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

TAB2 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | other |
| [Alpha-protein kinase 1 signaling pathway](https://reactome.org/content/detail/R-HSA-9645460) | other |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | other |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | other |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | other |
| [IRAK2 mediated activation of TAK1 complex](https://reactome.org/content/detail/R-HSA-937042) | other |
| [IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975163) | other |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | other |
| [JNK (c-Jun kinases) phosphorylation and  activation mediated by activated human TAK1](https://reactome.org/content/detail/R-HSA-450321) | other |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | other |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | other |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | other |
| [TICAM1,TRAF6-dependent induction of TAK1 complex](https://reactome.org/content/detail/R-HSA-9014325) | other |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | other |
| [TRAF6-mediated induction of TAK1 complex within TLR4 complex](https://reactome.org/content/detail/R-HSA-937072) | other |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | other |

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

**Molecular function:** zinc ion binding, molecular adaptor activity, K63-linked polyubiquitin modification-dependent protein binding.

**Biological process:** inflammatory response, canonical NF-kappaB signal transduction, heart development, response to lipopolysaccharide, non-canonical NF-kappaB signal transduction, defense response to bacterium.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-28.

**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 | 2023-11-28 |

## 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 TAB2 variant pages (same residue, condition, or type): [TAB2 p.Ala618Val](/variant/tab2-p-ala618val), [TAB2 p.Arg72His](/variant/tab2-p-arg72his), [TAB2 p.Arg96Ser](/variant/tab2-p-arg96ser), [TAB2 p.Asn118Tyr](/variant/tab2-p-asn118tyr), [TAB2 p.Asn669Thr](/variant/tab2-p-asn669thr), [TAB2 p.Gln209Lys](/variant/tab2-p-gln209lys), [TAB2 p.Glu49Lys](/variant/tab2-p-glu49lys), [TAB2 p.Glu93Lys](/variant/tab2-p-glu93lys).

### 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 3173208). 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.*