# NM_000014.6(A2M):c.479A>T (p.Glu160Val)

https://sugi.bio/variant/a2m-p-glu160val

## Summary

**A2M p.Glu160Val (c.479A>T)** is classified **Uncertain significance** in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.2609); Ultra-rare (popmax 0.0653%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0653%, afr)

## For patients & families {#patients}

This is a change in the A2M 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 | [A2M](https://sugi.bio/atlas/gene/A2M/) |
| Protein change (HGVS p.) | p.Glu160Val |
| Coding change (HGVS c.) | c.479A>T |
| MANE Select transcript | [NM_000014](https://www.ncbi.nlm.nih.gov/nuccore/NM_000014) |
| Variant type | single nucleotide variant |
| Location | chr12:9112163-9112163 (GRCh38) |
| ClinVar | [VCV3318187](https://www.ncbi.nlm.nih.gov/clinvar/variation/3318187/) |

**All HGVS expressions:** `LRG_591:g.8800A>T`, `LRG_591t1:c.479A>T`, `NC_000012.11:g.9264759T>A`, `NC_000012.12:g.9112163T>A`, `NG_011717.2:g.8800A>T`, `NM_000014.6:c.479A>T`, `NM_001347423.2:c.479A>T`, `NM_001347424.2:c.179A>T`, `NM_001347425.2:c.29A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2609)
- REVEL 0.306 (indeterminate)
- SaProt LLR -9.385 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 5.007, GERP 2.73, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.2**. 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 0.84** across the covering region of the MANE Select transcript (9,067,826–9,115,849), spanning 48,023 bp. Chi-square p 4.5e-12. 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 (T>C, Δ0.26 donor 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 (gnomAD v4.1): grpmax **0.0653%** (afr) · FAF95 0.0507% · FAF99 0.0455% · 49/75,022 in the highest group · 55/1,613,668 alleles overall — ultra-rare (popmax 0.0653%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0653% | 1,531 |
| Admixed American | 0.00333% | 30,002 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) | 0.000254% | 393,224 |

*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}

**A2M** population constraint: LOEUF 0.765, pLI 9.7568e-20, missense-Z 2.7587. *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 81.61, 30% of residues very-high.

**13 experimental structure(s)** (PDB): [1BV8](https://www.rcsb.org/structure/1BV8), [2P9R](https://www.rcsb.org/structure/2P9R), [6TAV](https://www.rcsb.org/structure/6TAV), [7O7L](https://www.rcsb.org/structure/7O7L), [7O7M](https://www.rcsb.org/structure/7O7M), [7O7N](https://www.rcsb.org/structure/7O7N).

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

*Describes the biological roles of A2M (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:** A2M's established molecular role includes protease binding.


### Pathways affected {#pathways}

A2M participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [HDL assembly](https://reactome.org/content/detail/R-HSA-8963896) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of FXIIa and plasma kallikrein activity](https://reactome.org/content/detail/R-HSA-9855719) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Molecular function:** protease binding, endopeptidase inhibitor activity, serine-type endopeptidase inhibitor activity, signaling receptor binding, growth factor binding, enzyme binding.

**Biological process:** negative regulation of complement activation, lectin pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-10.

**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 | 2024-06-10 |

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

## Similar variants {#similar}

Related A2M variant pages (same residue, condition, or type): [A2M c.3756+4G>A](/variant/a2m-c-3756-plus-4g-a), [A2M p.Ala844=](/variant/a2m-p-ala844), [A2M p.Asp277Asn](/variant/a2m-p-asp277asn), [A2M p.Ile1000Val](/variant/a2m-p-ile1000val), [A2M p.Pro261Leu](/variant/a2m-p-pro261leu), [A2M p.Tyr1152=](/variant/a2m-p-tyr1152), [A2M p.Val120=](/variant/a2m-p-val120), [A2M p.Val129=](/variant/a2m-p-val129).

### 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 3318187). 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.*