# NM_001292034.3(TAB2):c.203T>C (p.Ile68Thr)

https://sugi.bio/variant/tab2-p-ile68thr

## Summary

**TAB2 p.Ile68Thr (c.203T>C)** is classified **Uncertain significance** in TAB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-18). AlphaMissense: ambiguous (0.375); Very rare (popmax 8.47e-05%, nfe); Associated with congenital heart defects, multiple types, 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2483383686 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 8.47e-05%, nfe)

## 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 2 submitters, and is linked to congenital heart defects, multiple types, 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024964/index) · [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.Ile68Thr |
| Coding change (HGVS c.) | c.203T>C |
| MANE Select transcript | [NM_001292034](https://www.ncbi.nlm.nih.gov/nuccore/NM_001292034) |
| dbSNP | [rs2483383686](https://www.ncbi.nlm.nih.gov/snp/rs2483383686/) |
| Variant type | single nucleotide variant |
| Location | chr6:149378118-149378118 (GRCh38) |
| ClinVar | [VCV1803739](https://www.ncbi.nlm.nih.gov/clinvar/variation/1803739/) |

**All HGVS expressions:** `NC_000006.11:g.149699254T>C`, `NC_000006.12:g.149378118T>C`, `NG_021386.2:g.165195T>C`, `NM_001292034.3:c.203T>C`, `NM_001292035.3:c.107T>C`, `NM_001369506.1:c.203T>C`, `NM_015093.6:c.203T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.375) — no call either way
- REVEL 0.334 (indeterminate)
- SaProt LLR -8.003 (tolerated)
- Conservation: phyloP 7.917, GERP 1.78, phastCons 1 — highly conserved
- CADD: **PHRED 19.23**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TAB2 (720 scored positions, the nearest 12 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,020 in the highest group · 1/1,614,192 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}


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. 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-18.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Uncertain significance | criteria provided, single submitter | research | 2021-11-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-18 |

## Associated conditions {#conditions}

[congenital heart defects, multiple types, 2](https://sugi.bio/atlas/disease/congenital-heart-defects-multiple-types-2/).

**Reported phenotype names (ClinVar):** Congenital heart defects, multiple types, 2, not provided, none provided, Congenital heart defects, nonsyndromic, 2.

## Similar variants {#similar}

Related TAB2 variant pages (same residue, condition, or type): [TAB2 c.1764+1G>A](/variant/tab2-c-1764-plus-1g-a), [TAB2 p.Arg574Ter](/variant/tab2-p-arg574ter), [TAB2 p.Arg96Lys](/variant/tab2-p-arg96lys), [TAB2 p.His6Arg](/variant/tab2-p-his6arg), [TAB2 p.Ser50Asn](/variant/tab2-p-ser50asn), [TAB2 p.Gln7=](/variant/tab2-p-gln7), [TAB2 p.Gln127Ter](/variant/tab2-p-gln127ter), [TAB2 p.Pro183Leu](/variant/tab2-p-pro183leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1803739). 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.*