# NM_004357.5(CD151):c.259C>T (p.Arg87Trp)

https://sugi.bio/variant/cd151-p-arg87trp

## Summary

**CD151 p.Arg87Trp (c.259C>T)** is classified **Uncertain significance** in CD151 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-07). AlphaMissense: likely benign (0.2617); Very rare (popmax 0.00668%, afr); Associated with epidermolysis bullosa simplex 7, with nephropathy and deafness.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00668%, afr)

## For patients & families {#patients}

This is a change in the CD151 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to epidermolysis bullosa simplex 7, with nephropathy and deafness.

*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) | Adolescent |
| Diagnostic panels | CD151 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017367/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD151](https://sugi.bio/atlas/gene/CD151/) |
| Protein change (HGVS p.) | p.Arg87Trp |
| Coding change (HGVS c.) | c.259C>T |
| MANE Select transcript | [NM_004357](https://www.ncbi.nlm.nih.gov/nuccore/NM_004357) |
| Variant type | single nucleotide variant |
| Location | chr11:836425-836425 (GRCh38) |
| ClinVar | [VCV3574088](https://www.ncbi.nlm.nih.gov/clinvar/variation/3574088/) |

**All HGVS expressions:** `LRG_817:g.8474C>T`, `LRG_817t1:c.259C>T`, `NC_000011.10:g.836425C>T`, `NC_000011.9:g.836425C>T`, `NG_007478.1:g.8474C>T`, `NM_001039490.2:c.259C>T`, `NM_004357.5:c.259C>T`, `NM_139029.2:c.259C>T`, `NM_139030.4:c.259C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2617)
- REVEL 0.613 (indeterminate)
- SaProt LLR -10.747 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 0.105, GERP -2.12, phastCons 0.886 — weakly conserved position
- CADD: **PHRED 25.4**. 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 0.94** across the covering region of the MANE Select transcript (836,070–838,189), spanning 2,119 bp. Chi-square p 0.3. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.29 donor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00668%** (afr) · FAF95 0.00255% · FAF99 0.00162% · 5/74,902 in the highest group · 45/1,609,240 alleles overall — very rare (popmax 0.00668%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0678% | 1,475 |
| African / African-American (grpmax) | 0.00668% | 14,980 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,183 |
| Admixed American | 0.00167% | 59,904 |
| European (non-Finnish) | 0.00136% | 73,705 |
| South Asian | 0.0011% | 90,958 |

Ashkenazi Jewish 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}

**CD151** population constraint: LOEUF 0.816, pLI 0.00056955, missense-Z 0.62523. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.02, 68% of residues very-high.

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

*Describes the biological roles of CD151 (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:** CD151's established molecular role includes integrin binding.


### Pathways affected {#pathways}

CD151 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |

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

**Molecular function:** integrin binding.

**Biological process:** positive regulation of cell migration, wound healing, spreading of cells, positive regulation of endocytosis.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-07.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-02 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-07 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex 7, with nephropathy and deafness](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-7-with-nephropathy-and-deafness/).

**Reported phenotype names (ClinVar):** Epidermolysis bullosa simplex 7, with nephropathy and deafness, RAPH BLOOD GROUP SYSTEM, not provided, Nephrotic syndrome - deafness - pretibial epidermolysis bullosa syndrome, Nephropathy with Pretibial Epidermolysis Bullosa and Deafness, MER2 BLOOD CELL ANTIGEN EXPRESSION, none provided.

## Similar variants {#similar}

Related CD151 variant pages (same residue, condition, or type): [CD151 p.Arg87Gly](/variant/cd151-p-arg87gly), [CD151 p.Arg87=](/variant/cd151-p-arg87), [CD151 p.Arg87Leu](/variant/cd151-p-arg87leu), [CD151 p.Lys7Ter](/variant/cd151-p-lys7ter), [CD151 c.352-11C>G](/variant/cd151-c-352-minus-11c-g), [CD151 c.702+4A>G](/variant/cd151-c-702-plus-4a-g), [CD151 c.702+5G>C](/variant/cd151-c-702-plus-5g-c), [CD151 p.Ala145Thr](/variant/cd151-p-ala145thr).

### 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 3574088). 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.*