# NM_000014.6(A2M):c.1644C>T (p.Thr548=)

https://sugi.bio/variant/a2m-p-thr548

## Summary

**A2M p.Thr548= (c.1644C>T)** is classified **Likely benign** in A2M (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-07). Ultra-rare (popmax 0.012%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs745823596 · 2 submitters · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the A2M gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Thr548= |
| Coding change (HGVS c.) | c.1644C>T |
| MANE Select transcript | [NM_000014](https://www.ncbi.nlm.nih.gov/nuccore/NM_000014) |
| dbSNP | [rs745823596](https://www.ncbi.nlm.nih.gov/snp/rs745823596/) |
| Variant type | single nucleotide variant |
| Location | chr12:9099438-9099438 (GRCh38) |
| ClinVar | [VCV3057371](https://www.ncbi.nlm.nih.gov/clinvar/variation/3057371/) |

**All HGVS expressions:** `LRG_591:g.21525C>T`, `LRG_591t1:c.1644C>T`, `NC_000012.11:g.9252034G>A`, `NC_000012.12:g.9099438G>A`, `NG_011717.2:g.21525C>T`, `NM_000014.6:c.1644C>T`, `NM_001347423.2:c.1644C>T`, `NM_001347424.2:c.1344C>T`, `NM_001347425.2:c.1194C>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.481, GERP -3.44 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.645**. 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 (G>T, Δ0.72 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 (gnomAD v4.1): grpmax **0.012%** (afr) · FAF95 0.00625% · FAF99 0.00468% · 9/74,766 in the highest group · 39/1,597,934 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.012% | 8,307 |
| South Asian | 0.0057% | 17,556 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00341% | 29,312 |
| East Asian | 0.00225% | 44,390 |
| European (non-Finnish) | 0.00188% | 53,271 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,012 |

*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}

Residue **548** lies in a disulfide bond.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-07.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-07 |

**Reported phenotype names (ClinVar):** A2M-related disorder, not specified, A2M-related condition, 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 3057371). 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.*