# NM_005191.4(CD80):c.857G>A (p.Arg286His)

https://sugi.bio/variant/cd80-p-arg286his

## Summary

**CD80 p.Arg286His (c.857G>A)** is classified **Uncertain significance** in CD80 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely benign (0.1198); Very rare (popmax 0.00271%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00271%, nfe)

## For patients & families {#patients}

This is a change in the CD80 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD80](https://sugi.bio/atlas/gene/CD80/) |
| Protein change (HGVS p.) | p.Arg286His |
| Coding change (HGVS c.) | c.857G>A |
| MANE Select transcript | [NM_005191](https://www.ncbi.nlm.nih.gov/nuccore/NM_005191) |
| Variant type | single nucleotide variant |
| Location | chr3:119527781-119527781 (GRCh38) |
| ClinVar | [VCV3829635](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829635/) |

**All HGVS expressions:** `NC_000003.11:g.119246628C>T`, `NC_000003.12:g.119527781C>T`, `NM_005191.4:c.857G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1198)
- REVEL 0.076 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.022 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.144, GERP -3.76 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.86**. 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 0.80** across the covering region of the MANE Select transcript (119,527,774–119,557,728), spanning 29,954 bp. Chi-square p 0.00015. 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>G, Δ0.22 donor 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00271%** (nfe) · FAF95 0.00196% · FAF99 0.00168% · 32/1,179,622 in the highest group · 35/1,613,538 alleles overall — very rare (popmax 0.00271%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00271% | 36,863 |
| Admixed American | 0.00167% | 59,990 |
| African / African-American | 0.00134% | 74,882 |
| South Asian | 0.0011% | 91,072 |

*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}

**CD80** population constraint: LOEUF 0.818, pLI 0.10245, missense-Z 1.4654. *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 86.17, 65% of residues very-high.

**6 experimental structure(s)** (PDB): [1DR9](https://www.rcsb.org/structure/1DR9), [1I8L](https://www.rcsb.org/structure/1I8L), [7TPS](https://www.rcsb.org/structure/7TPS), [8FXW](https://www.rcsb.org/structure/8FXW), [8FXZ](https://www.rcsb.org/structure/8FXZ), [8HXA](https://www.rcsb.org/structure/8HXA).

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

*Describes the biological roles of CD80 (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:** CD80's established molecular role includes receptor ligand activity. In Reactome, CD80 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** CD80 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

CD80 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | curated |
| [CD28 dependent Vav1 pathway](https://reactome.org/content/detail/R-HSA-389359) | curated |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | curated |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |

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

**Molecular function:** receptor ligand activity.

**Biological process:** negative regulation of T cell mediated immunity, T cell activation, positive regulation of peptidyl-tyrosine phosphorylation, positive regulation of T cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-18 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD80 variant pages (same residue, condition, or type): [CD80 p.Arg286Cys](/variant/cd80-p-arg286cys), [CD80 c.*214T>G](/variant/cd80-c-star-214t-g), [CD80 p.His222Tyr](/variant/cd80-p-his222tyr), [CD80 p.Arg107His](/variant/cd80-p-arg107his), [CD80 p.Arg128Gln](/variant/cd80-p-arg128gln), [CD80 p.Arg224Lys](/variant/cd80-p-arg224lys), [CD80 p.Arg63Cys](/variant/cd80-p-arg63cys), [CD80 p.Asn183Asp](/variant/cd80-p-asn183asp).

### 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 3829635). 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.*