# NM_000593.6(TAP1):c.423T>C (p.Val141=)

https://sugi.bio/variant/tap1-p-val141

## Summary

**TAP1 p.Val141= (c.423T>C)** is classified **Benign** in TAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Common (popmax 6.12%, sas) — too common for a highly-penetrant pathogenic allele; Associated with MHC class I deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs55702652 · 2 submitters · 1 linked condition · common (popmax 6.12%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TAP1 gene that is classified as benign — not considered disease-causing, submitted by 2 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 | TAP1 is a diagnostic-grade gene on 2 Genomics England panels |

**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 | [TAP1](https://sugi.bio/atlas/gene/TAP1/) |
| Protein change (HGVS p.) | p.Val141= |
| Coding change (HGVS c.) | c.423T>C |
| MANE Select transcript | [NM_000593](https://www.ncbi.nlm.nih.gov/nuccore/NM_000593) |
| dbSNP | [rs55702652](https://www.ncbi.nlm.nih.gov/snp/rs55702652/) |
| Variant type | single nucleotide variant |
| Location | chr6:32853214-32853214 (GRCh38) |
| ClinVar | [VCV466389](https://www.ncbi.nlm.nih.gov/clinvar/variation/466389/) |

**All HGVS expressions:** `LRG_166:g.5758T>C`, `LRG_166t1:c.423T>C`, `NC_000006.11:g.32820991A>G`, `NC_000006.12:g.32853214A>G`, `NG_011759.1:g.5758T>C`, `NM_000593.6:c.423T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.12%, sas) — 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 0.043, GERP -2.5 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.258**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **6.12%** (sas) · FAF95 5.98% · FAF99 5.93% · 5,547/90,676 in the highest group · 50,234/1,611,216 alleles overall — common (popmax 6.12%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 11.3% | 9 |
| South Asian (grpmax) | 6.12% | 16 |
| Finnish (not grpmax-eligible) | 3.44% | 29 |
| African / African-American | 3.27% | 31 |
| European (non-Finnish) | 3.14% | 32 |
| Remaining individuals (not grpmax-eligible) | 2.74% | 37 |
| Admixed American | 1.46% | 69 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.05% | 95 |
| Middle Eastern | 0.792% | 126 |
| East Asian | 0.0892% | 1,121 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**TAP1** population constraint: LOEUF 0.876, pLI 1.4922e-13, missense-Z 2.6869. *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** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.03, 27% of residues very-high.

**22 experimental structure(s)** (PDB): [1JJ7](https://www.rcsb.org/structure/1JJ7), [5U1D](https://www.rcsb.org/structure/5U1D), [8T46](https://www.rcsb.org/structure/8T46), [8T4E](https://www.rcsb.org/structure/8T4E), [8T4F](https://www.rcsb.org/structure/8T4F), [8T4G](https://www.rcsb.org/structure/8T4G) — incl. mutant structure 9N62.

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

*Describes the biological roles of TAP1 (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:** TAP1's established molecular role includes ATP binding.


### Pathways affected {#pathways}

TAP1 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) | electronic |

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

**Molecular function:** ATP binding, ABC-type peptide antigen transporter activity, MHC class Ib protein binding, peptide antigen binding, ADP binding, TAP2 binding.

**Biological process:** peptide transport, antigen processing and presentation of endogenous peptide antigen via MHC class I, cytosol to endoplasmic reticulum transport.

## Clinical significance {#significance}

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

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 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, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TAP1 variant pages (same residue, condition, or type): [TAP1 p.Arg378Ter](/variant/tap1-p-arg378ter), [TAP1 p.Gln522Ter](/variant/tap1-p-gln522ter), [TAP1 c.-20G>C](/variant/tap1-c-minus-20g-c), [TAP1 c.-59C>T](/variant/tap1-c-minus-59c-t), [TAP1 p.Ala101Val](/variant/tap1-p-ala101val), [TAP1 p.Ala2Thr](/variant/tap1-p-ala2thr), [TAP1 p.Ala59Thr](/variant/tap1-p-ala59thr), [TAP1 p.Arg129Lys](/variant/tap1-p-arg129lys).

### 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 466389). 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.*