# NM_003190.5(TAPBP):c.1239C>T (p.Ser413=)

https://sugi.bio/variant/tapbp-p-ser413

## Summary

**TAPBP p.Ser413= (c.1239C>T)** is classified **Benign** in TAPBP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with MHC class I deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs34132052 · 3 submitters · 1 linked condition · common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TAPBP gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to MHC class I deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | TAPBP is a diagnostic-grade gene on 1 Genomics England panel |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009548/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TAPBP](https://sugi.bio/atlas/gene/TAPBP/) |
| Protein change (HGVS p.) | p.Ser413= |
| Coding change (HGVS c.) | c.1239C>T |
| MANE Select transcript | [NM_003190](https://www.ncbi.nlm.nih.gov/nuccore/NM_003190) |
| dbSNP | [rs34132052](https://www.ncbi.nlm.nih.gov/snp/rs34132052/) |
| Variant type | single nucleotide variant |
| Location | chr6:33304189-33304189 (GRCh38) |
| ClinVar | [VCV466396](https://www.ncbi.nlm.nih.gov/clinvar/variation/466396/) |

**All HGVS expressions:** `LRG_114:g.15024C>T`, `LRG_114t1:c.1239C>T`, `NC_000006.11:g.33271966G>A`, `NC_000006.12:g.33304189G>A`, `NG_009876.1:g.15024C>T`, `NM_003190.5:c.1239C>T`, `NM_172208.3:c.1239C>T`, `NM_172209.3:c.978C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -2.643, GERP -2.92 — fast-evolving / accelerated position
- CADD: **PHRED 1.669**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.25 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.23** (loss), gain 0.01 / loss 0.23. SpliceAI below 0.2. 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 **12.1%** (afr) · FAF95 11.9% · FAF99 11.8% · 9,063/74,818 in the highest group · 10,447/1,613,574 alleles overall — common (popmax 12.1%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 12.1% | 8 |
| Middle Eastern | 0.841% | 119 |
| Remaining individuals (not grpmax-eligible) | 0.768% | 130 |
| Admixed American | 0.729% | 137 |
| South Asian | 0.126% | 792 |
| European (non-Finnish) | 0.0255% | 3,920 |

*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}

**TAPBP** population constraint: LOEUF 1.061, pLI 1.8386e-11, missense-Z 1.3653. *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):

- **MHC class I deficiency** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.71, 66% of residues very-high.

**12 experimental structure(s)** (PDB): [3F8U](https://www.rcsb.org/structure/3F8U), [6ENY](https://www.rcsb.org/structure/6ENY), [7QNG](https://www.rcsb.org/structure/7QNG), [7QPD](https://www.rcsb.org/structure/7QPD), [7TUE](https://www.rcsb.org/structure/7TUE), [7TUF](https://www.rcsb.org/structure/7TUF).

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

*Describes the biological roles of TAPBP (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:** TAPBP's established molecular role includes protein folding chaperone.


### Pathways affected {#pathways}

TAPBP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen Presentation: Folding, assembly and peptide loading of class I MHC](https://reactome.org/content/detail/R-HSA-983170) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |

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

**Molecular function:** protein folding chaperone, TAP1 binding, TAP2 binding, molecular adaptor activity, TAP complex binding.

**Biological process:** MHC class Ib protein complex assembly, peptide antigen assembly with MHC class I protein complex, regulation of gene expression, regulation of protein complex stability, protein-containing complex assembly.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |

## Associated conditions {#conditions}

[MHC class I deficiency](https://sugi.bio/atlas/disease/mhc-class-i-deficiency/).

**Reported phenotype names (ClinVar):** MHC class I deficiency, TAPBP-related disorder, not specified, AllHighlyPenetrant, TAPBP-related condition.

## Similar variants {#similar}

Related TAPBP variant pages (same residue, condition, or type): [TAPBP p.Ala191Thr](/variant/tapbp-p-ala191thr), [TAPBP p.Ala220Val](/variant/tapbp-p-ala220val), [TAPBP p.Ala305Ser](/variant/tapbp-p-ala305ser), [TAPBP p.Ala305Thr](/variant/tapbp-p-ala305thr), [TAPBP p.Ala309Glu](/variant/tapbp-p-ala309glu), [TAPBP p.Ala396Thr](/variant/tapbp-p-ala396thr), [TAPBP p.Ala433Thr](/variant/tapbp-p-ala433thr), [TAPBP p.Arg208Cys](/variant/tapbp-p-arg208cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 466396). 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.*