# NM_004357.5(CD151):c.493C>T (p.Arg165Ter)

https://sugi.bio/variant/cd151-p-arg165ter

## Summary

**CD151 p.Arg165Ter (c.493C>T)** is classified **Conflicting classifications of pathogenicity** in CD151 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-14). Very rare (popmax 0.00223%, eas); Associated with epidermolysis bullosa simplex 7, with nephropathy and deafness.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs759213580 · 5 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CD151 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Arg165Ter |
| Coding change (HGVS c.) | c.493C>T |
| MANE Select transcript | [NM_004357](https://www.ncbi.nlm.nih.gov/nuccore/NM_004357) |
| dbSNP | [rs759213580](https://www.ncbi.nlm.nih.gov/snp/rs759213580/) |
| Variant type | single nucleotide variant |
| Location | chr11:837496-837496 (GRCh38) |
| ClinVar | [VCV1028736](https://www.ncbi.nlm.nih.gov/clinvar/variation/1028736/) |

**All HGVS expressions:** `LRG_817:g.9545C>T`, `LRG_817t1:c.493C>T`, `NC_000011.10:g.837496C>T`, `NC_000011.9:g.837496C>T`, `NG_007478.1:g.9545C>T`, `NM_001039490.2:c.493C>T`, `NM_004357.5:c.493C>T`, `NM_139029.2:c.493C>T`, `NM_139030.4:c.493C>T`

## Computational & population evidence {#evidence}

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

- **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 -1.064, GERP -3.29 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.816, pLI 0.00056955. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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 **0.00223%** (eas) · FAF95 0.000688% · FAF99 0.000539% · 1/44,870 in the highest group · 16/1,460,622 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,870 |
| European (non-Finnish) | 0.00119% | 84,283 |
| South Asian | 0.0011% | 91,070 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-14.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Uncertain significance).

**Submission history:** 5 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-06-09 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2021-01-04 |
| Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Pathogenic | no assertion criteria provided | clinical testing | 2020-06-09 |
| Daryl Scott Lab, Baylor College of Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-14 |

## 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, not provided, none provided, Nephrotic syndrome - deafness - pretibial epidermolysis bullosa syndrome, Nephropathy with Pretibial Epidermolysis Bullosa and Deafness.

## Similar variants {#similar}

Related CD151 variant pages (same residue, condition, or type): [CD151 p.Arg165Gln](/variant/cd151-p-arg165gln), [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), [CD151 p.Ala81Thr](/variant/cd151-p-ala81thr), [CD151 p.Arg133Cys](/variant/cd151-p-arg133cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1028736). 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.*