# NM_004048.4(B2M):c.349C>A (p.Arg117=)

https://sugi.bio/variant/b2m-p-arg117

## Summary

**B2M p.Arg117= (c.349C>A)** is classified **Likely benign** in B2M (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). Very rare (popmax 8.48e-05%, nfe); Associated with hypoproteinemia, hypercatabolic.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the B2M gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hypoproteinemia, hypercatabolic.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015185/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [B2M](https://sugi.bio/atlas/gene/B2M/) |
| Protein change (HGVS p.) | p.Arg117= |
| Coding change (HGVS c.) | c.349C>A |
| MANE Select transcript | [NM_004048](https://www.ncbi.nlm.nih.gov/nuccore/NM_004048) |
| Variant type | single nucleotide variant |
| Location | chr15:44716331-44716331 (GRCh38) |
| ClinVar | [VCV4811830](https://www.ncbi.nlm.nih.gov/clinvar/variation/4811830/) |

**All HGVS expressions:** `LRG_1215:g.9855C>A`, `LRG_1215t1:c.349C>A`, `NC_000015.10:g.44716331C>A`, `NC_000015.9:g.45008529C>A`, `NG_012920.2:g.9855C>A`, `NM_004048.4:c.349C>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 0.36) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.855, GERP 0.941 — weakly conserved position
- CADD: **PHRED 17.73**. 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 **0.01**, donor loss **0.03**, acceptor gain **0.36**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,178,574 in the highest group · 1/1,612,390 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**B2M** population constraint: LOEUF 0.501, pLI 0.96577, missense-Z 1.2604. *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):

- **hypoproteinemia, hypercatabolic** — Limited (AR)
- **amyloidosis, hereditary systemic 6** — Limited (AD)

## Protein context {#protein}

Residue **117** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 94.43, 85% of residues very-high.

**1396 experimental structure(s)** (PDB): [1A1M](https://www.rcsb.org/structure/1A1M), [1A1N](https://www.rcsb.org/structure/1A1N), [1A1O](https://www.rcsb.org/structure/1A1O), [1A6Z](https://www.rcsb.org/structure/1A6Z), [1A9B](https://www.rcsb.org/structure/1A9B), [1A9E](https://www.rcsb.org/structure/1A9E) — incl. mutant structure 1EEZ.

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

*Describes the biological roles of B2M (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:** B2M's established molecular role includes structural molecule activity. In Reactome, B2M is annotated in disease pathway(s) including **Modulation by Mtb of host immune system**, **Nef mediated downregulation of MHC class I complex cell surface expression**.

**Disease mechanism (Reactome):** B2M loss or alteration is curated in [Modulation by Mtb of host immune system](https://reactome.org/content/detail/R-HSA-9637628), [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

B2M participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Modulation by Mtb of host immune system](https://reactome.org/content/detail/R-HSA-9637628) | curated |
| ⚕ [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [Antigen Presentation: Folding, assembly and peptide loading of class I MHC](https://reactome.org/content/detail/R-HSA-983170) | curated |
| [DAP12 interactions](https://reactome.org/content/detail/R-HSA-2172127) | curated |
| [Endosomal/Vacuolar pathway](https://reactome.org/content/detail/R-HSA-1236977) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | electronic |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | electronic |

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

**Molecular function:** structural molecule activity, identical protein binding, protein homodimerization activity.

**Biological process:** antigen processing and presentation of exogenous peptide antigen via MHC class Ib, peptide antigen assembly with MHC class I protein complex, positive regulation of T cell cytokine production, intracellular iron ion homeostasis, learning or memory, antigen processing and presentation of endogenous peptide antigen via MHC class I.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-27.

**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 | 2025-03-27 |

## Associated conditions {#conditions}

[hypoproteinemia, hypercatabolic](https://sugi.bio/atlas/disease/hypoproteinemia-hypercatabolic/).

**Reported phenotype names (ClinVar):** Hypoproteinemia, hypercatabolic, MHC CLASS I DEFICIENCY 4, IMMUNODEFICIENCY 43, BETA-2-MICROGLOBULIN DEFICIENCY, B2M DEFICIENCY.

## Similar variants {#similar}

Related B2M variant pages (same residue, condition, or type): [B2M p.Asp54Asn](/variant/b2m-p-asp54asn), [B2M p.Ile55Thr](/variant/b2m-p-ile55thr), [B2M p.Lys114Gln](/variant/b2m-p-lys114gln), [B2M p.Lys68Glu](/variant/b2m-p-lys68glu), [B2M p.Pro92Leu](/variant/b2m-p-pro92leu), [B2M c.67+12C>T](/variant/b2m-c-67-plus-12c-t), [B2M c.67+19C>T](/variant/b2m-c-67-plus-19c-t), [B2M c.68-13C>T](/variant/b2m-c-68-minus-13c-t).

### 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 4811830). 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.*