# NM_030943.4(AMN):c.168_169dup (p.Ser57fs)

https://sugi.bio/variant/amn-p-ser57fs

## Summary

**AMN p.Ser57fs (c.168_169dup)** is classified **Likely pathogenic** in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2017-07-19). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1555380625 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AMN gene that is considered likely 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 | [AMN](https://sugi.bio/atlas/gene/AMN/) |
| Protein change (HGVS p.) | p.Ser57fs |
| Coding change (HGVS c.) | c.168_169dup |
| MANE Select transcript | [NM_030943](https://www.ncbi.nlm.nih.gov/nuccore/NM_030943) |
| dbSNP | [rs1555380625](https://www.ncbi.nlm.nih.gov/snp/rs1555380625/) |
| Variant type | Microsatellite |
| Location | chr14:102923937-102923938 (GRCh38) |
| ClinVar | [VCV419161](https://www.ncbi.nlm.nih.gov/clinvar/variation/419161/) |

**All HGVS expressions:** `LRG_642:g.6283GT[3]`, `NC_000014.8:g.103390275GT[3]`, `NC_000014.9:g.102923938GT[3]`, `NG_008276.2:g.6283GT[3]`, `NM_030943.3:c.168_169dupGT`, `NM_030943.4:c.168_169dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.531, GERP -0.026, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.446, pLI 1.8277e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**AMN** population constraint: LOEUF 1.446, pLI 1.8277e-15, missense-Z -2.732; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **57** lies in a β-strand; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 80.78, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [6GJE](https://www.rcsb.org/structure/6GJE).

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

*Describes the biological roles of AMN (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:** AMN's established molecular role includes signaling receptor binding. In Reactome, AMN is annotated in disease pathway(s) including **Defective AMN causes MGA1**, **Defective CUBN causes MGA1**.

**Disease mechanism (Reactome):** AMN loss or alteration is curated in [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462), [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463).

### Pathways affected {#pathways}

AMN participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462) | other |
| ⚕ [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463) | other |
| [HDL clearance](https://reactome.org/content/detail/R-HSA-8964011) | other |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | other |

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

**Molecular function:** signaling receptor binding, cargo receptor activity.

**Biological process:** receptor-mediated endocytosis, cobalamin metabolic process, cobalamin transport, Golgi to plasma membrane protein transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-07-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-07-19 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Same-residue context {#hotspot}

Residue **57** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AMN p.Ser57Ter](/variant/amn-p-ser57ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AMN variant pages (same residue, condition, or type): [AMN p.Ser57Ter](/variant/amn-p-ser57ter), [AMN c.44-7_44-5del](/variant/amn-c-44-minus-7-44-minus-5del), [AMN p.Asp108fs](/variant/amn-p-asp108fs), [AMN p.His438fs](/variant/amn-p-his438fs), [AMN p.Gly46del](/variant/amn-p-gly46del), [AMN p.Ser292fs](/variant/amn-p-ser292fs), [AMN p.450EA[3]](/variant/amn-p-450ea-3).

### 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 419161). 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.*