# NM_004356.4(CD81):c.276G>T (p.Gly92=)

https://sugi.bio/variant/cd81-p-gly92

## Summary

**CD81 p.Gly92= (c.276G>T)** is classified **Uncertain significance** in CD81 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-08). Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CD81 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 | [CD81](https://sugi.bio/atlas/gene/CD81/) |
| Protein change (HGVS p.) | p.Gly92= |
| Coding change (HGVS c.) | c.276G>T |
| MANE Select transcript | [NM_004356](https://www.ncbi.nlm.nih.gov/nuccore/NM_004356) |
| Variant type | single nucleotide variant |
| Location | chr11:2394189-2394189 (GRCh38) |
| ClinVar | [VCV3637939](https://www.ncbi.nlm.nih.gov/clinvar/variation/3637939/) |

**All HGVS expressions:** `LRG_142:g.21873G>T`, `LRG_142t1:c.276G>T`, `NC_000011.10:g.2394189G>T`, `NC_000011.9:g.2415419G>T`, `NG_023386.1:g.21873G>T`, `NM_001297649.2:c.63G>T`, `NM_001425129.1:c.63G>T`, `NM_001425130.1:c.63G>T`, `NM_001425131.1:c.63G>T`, `NM_001425132.1:c.63G>T`, `NM_001425134.1:c.63G>T`, `NM_001425135.1:c.276G>T`, `NM_001425137.1:c.276G>T`, `NM_001425138.1:c.63G>T`, `NM_004356.4:c.276G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.96) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.456, GERP -3.99, phastCons 0.99 — weakly conserved position
- CADD: **PHRED 21.5**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.96**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.96**.
- Pangolin: Δ**0.62** (gain), gain 0.62 / loss 0.08. Agrees with SpliceAI. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CD81** population constraint: LOEUF 0.702, pLI 0.35955, missense-Z 1.0663. *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):

- **immunodeficiency, common variable, 6** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.24, 62% of residues very-high.

**16 experimental structure(s)** (PDB): [1G8Q](https://www.rcsb.org/structure/1G8Q), [1IV5](https://www.rcsb.org/structure/1IV5), [3X0E](https://www.rcsb.org/structure/3X0E), [5DFV](https://www.rcsb.org/structure/5DFV), [5DFW](https://www.rcsb.org/structure/5DFW), [5M2C](https://www.rcsb.org/structure/5M2C).

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

*Describes the biological roles of CD81 (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:** CD81's established molecular role includes virus receptor activity.


### Pathways affected {#pathways}

CD81 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** virus receptor activity, integrin binding, cholesterol binding, MHC class II protein complex binding, MHC class II protein binding, transferrin receptor binding.

**Biological process:** immunological synapse formation, humoral immune response mediated by circulating immunoglobulin, positive regulation of B cell proliferation, regulation of protein stability, macrophage fusion, CD4-positive, alpha-beta T cell costimulation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-08 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CD81 variant pages (same residue, condition, or type): [CD81 p.Gly92Glu](/variant/cd81-p-gly92glu), [CD81 c.561+5G>A](/variant/cd81-c-561-plus-5g-a), [CD81 p.Ala120Thr](/variant/cd81-p-ala120thr), [CD81 p.Ala54Val](/variant/cd81-p-ala54val), [CD81 p.Arg231Gln](/variant/cd81-p-arg231gln), [CD81 p.Asn115Ser](/variant/cd81-p-asn115ser), [CD81 p.Asn141Lys](/variant/cd81-p-asn141lys), [CD81 p.Asn141Ser](/variant/cd81-p-asn141ser).

### 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 3637939). 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.*