# NM_001770.6(CD19):c.381G>A (p.Ser127=)

https://sugi.bio/variant/cd19-p-ser127

## Summary

**CD19 p.Ser127= (c.381G>A)** is classified **Benign/Likely benign** in CD19 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). Rare (popmax 0.789%, nfe); Associated with immunodeficiency, common variable, 3.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs142342927 · 7 submitters · 1 linked condition · rare (popmax 0.789%, nfe)

## For patients & families {#patients}

This is a change in the CD19 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to immunodeficiency, common variable, 3.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | CD19 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015668/index) · [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.Ser127= |
| Coding change (HGVS c.) | c.381G>A |
| MANE Select transcript | [NM_001770](https://www.ncbi.nlm.nih.gov/nuccore/NM_001770) |
| dbSNP | [rs142342927](https://www.ncbi.nlm.nih.gov/snp/rs142342927/) |
| Variant type | single nucleotide variant |
| Location | chr16:28932936-28932936 (GRCh38) |
| ClinVar | [VCV318798](https://www.ncbi.nlm.nih.gov/clinvar/variation/318798/) |

**All HGVS expressions:** `LRG_35:g.5998G>A`, `LRG_35t1:c.381G>A`, `NC_000016.10:g.28932936G>A`, `NC_000016.9:g.28944257G>A`, `NG_007275.1:g.5998G>A`, `NM_001178098.2:c.381G>A`, `NM_001385732.1:c.114G>A`, `NM_001770.6:c.381G>A`, `NR_169755.1:n.709G>A`

## 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 **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.064, phastCons 0.104 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 13.24**. 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 **0.20**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.789%** (nfe) · FAF95 0.776% · FAF99 0.77% · 9,233/1,170,046 in the highest group · 10,544/1,593,238 alleles overall — rare (popmax 0.789%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.835% | 120 |
| European (non-Finnish) (grpmax) | 0.789% | 127 |
| Middle Eastern | 0.613% | 163 |
| Remaining individuals (not grpmax-eligible) | 0.54% | 185 |
| Amish (not grpmax-eligible) | 0.33% | 303 |
| African / African-American | 0.261% | 383 |
| Admixed American | 0.179% | 559 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.103% | 972 |
| South Asian | 0.101% | 993 |

Finnish 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}

**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}


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:** CD19 participates in disease-associated pathways. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (5 Likely benign, 1 Likely Benign, 1 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-02-24 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-09-27 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[immunodeficiency, common variable, 3](https://sugi.bio/atlas/disease/immunodeficiency-common-variable-3/).

**Reported phenotype names (ClinVar):** Immunodeficiency, common variable, 3, not provided, CD19-related disorder, not specified, AllHighlyPenetrant, ANTIBODY DEFICIENCY DUE TO CD19 DEFECT, none provided, CD19-related condition.

## 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.Arg163His](/variant/cd19-p-arg163his), [CD19 p.Arg263His](/variant/cd19-p-arg263his), [CD19 p.Arg490Gln](/variant/cd19-p-arg490gln), [CD19 p.Arg76Ser](/variant/cd19-p-arg76ser), [CD19 p.Gln345His](/variant/cd19-p-gln345his), [CD19 p.Glu21Gln](/variant/cd19-p-glu21gln), [CD19 p.Glu29Gln](/variant/cd19-p-glu29gln).

### 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 318798). 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.*