# NM_001770.6(CD19):c.1374T>G (p.Ala458=)

https://sugi.bio/variant/cd19-p-ala458

## Summary

**CD19 p.Ala458= (c.1374T>G)** is classified **Likely benign** in CD19 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-15). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs2506479187 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CD19 gene that is classified as likely benign — not considered disease-causing, 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 | [CD19](https://sugi.bio/atlas/gene/CD19/) |
| Protein change (HGVS p.) | p.Ala458= |
| Coding change (HGVS c.) | c.1374T>G |
| MANE Select transcript | [NM_001770](https://www.ncbi.nlm.nih.gov/nuccore/NM_001770) |
| dbSNP | [rs2506479187](https://www.ncbi.nlm.nih.gov/snp/rs2506479187/) |
| Variant type | single nucleotide variant |
| Location | chr16:28937625-28937625 (GRCh38) |
| ClinVar | [VCV2806310](https://www.ncbi.nlm.nih.gov/clinvar/variation/2806310/) |

**All HGVS expressions:** `LRG_35:g.10687T>G`, `LRG_35t1:c.1374T>G`, `NC_000016.10:g.28937625T>G`, `NC_000016.9:g.28948946T>G`, `NG_007275.1:g.10687T>G`, `NM_001178098.2:c.1374T>G`, `NM_001385732.1:c.1107T>G`, `NM_001770.6:c.1374T>G`, `NR_169755.1:n.1716T>G`

## 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 -2.991 — fast-evolving / accelerated position
- CADD: **PHRED 3.448**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.85 acceptor 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: **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}

**CD19** population constraint: LOEUF 0.627, pLI 0.0059088, missense-Z 1.3202; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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, 3** — Definitive (AR)

## Protein context {#protein}

Residue **458** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 62.99, 24% of residues very-high.

**4 experimental structure(s)** (PDB): [6AL5](https://www.rcsb.org/structure/6AL5), [7JIC](https://www.rcsb.org/structure/7JIC), [7URV](https://www.rcsb.org/structure/7URV), [7URX](https://www.rcsb.org/structure/7URX) — incl. mutant structure 6AL5.

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

*Describes the biological roles of CD19 (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:** p.Ala458= falls in the disordered region. In Reactome, CD19 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** CD19 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

CD19 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | 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 |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |

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

**Biological process:** B cell proliferation involved in immune response, immunoglobulin mediated immune response, antigen receptor-mediated signaling pathway, regulation of B cell receptor signaling pathway, regulation of B cell activation, positive regulation of release of sequestered calcium ion into cytosol.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-15 |

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

## Similar variants {#similar}

Related CD19 variant pages (same residue, condition, or type): [CD19 c.835+3A>G](/variant/cd19-c-835-plus-3a-g), [CD19 p.Ala191Thr](/variant/cd19-p-ala191thr), [CD19 p.Arg123Trp](/variant/cd19-p-arg123trp), [CD19 p.Arg163His](/variant/cd19-p-arg163his), [CD19 p.Arg234Cys](/variant/cd19-p-arg234cys), [CD19 p.Arg263His](/variant/cd19-p-arg263his), [CD19 p.Arg321Lys](/variant/cd19-p-arg321lys), [CD19 p.Arg490Gln](/variant/cd19-p-arg490gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2806310). 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.*