# NM_030943.4(AMN):c.311del (p.Phe104fs)

https://sugi.bio/variant/amn-p-phe104fs

## Summary

**AMN p.Phe104fs (c.311del)** is classified **Likely pathogenic** in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). Associated with Imerslund-Grasbeck syndrome type 2.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the AMN gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Imerslund-Grasbeck syndrome type 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Finland) |
| Diagnostic panels | AMN is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Imerslund-Gräsbeck syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased circulating vitamin B12 concentration — Obligate (100%)
- Malabsorption of Vitamin B12 — Obligate (100%)
- Abnormal blood 5-methyltetrahydrofolate level — Obligate (100%)
- Megaloblastic anemia — Very frequent (99-80%)
- Macrocytic anemia — Very frequent (99-80%)
- Hypersegmentation of neutrophil nuclei — Very frequent (99-80%)
- Proteinuria — Frequent (79-30%)
- Pallor — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026067/index) · [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.Phe104fs |
| Coding change (HGVS c.) | c.311del |
| MANE Select transcript | [NM_030943](https://www.ncbi.nlm.nih.gov/nuccore/NM_030943) |
| Variant type | Deletion |
| Location | chr14:102928772-102928772 (GRCh38) |
| ClinVar | [VCV4855611](https://www.ncbi.nlm.nih.gov/clinvar/variation/4855611/) |

**All HGVS expressions:** `LRG_642:g.11118del`, `LRG_642t1:c.311del`, `NC_000014.8:g.103395110del`, `NC_000014.9:g.102928773del`, `NG_008276.2:g.11118del`, `NM_001425246.1:c.149del`, `NM_030943.4:c.311del`

## 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 0.49, GERP 1.16, phastCons 0.547 — weakly conserved position
- 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 5 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **104** lies in a β-strand.

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 2025-05-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-16 |

## Associated conditions {#conditions}

[Imerslund-Grasbeck syndrome type 2](https://sugi.bio/atlas/disease/imerslund-grasbeck-syndrome-type-2/).

**Reported phenotype names (ClinVar):** Imerslund-Grasbeck syndrome type 2, Megaloblastic anemia 1, Norwegian type, MEGALOBLASTIC ANEMIA, NORWEGIAN TYPE, Imerslund-Gräsbeck syndrome 2.

## Similar variants {#similar}

Related AMN variant pages (same residue, condition, or type): [AMN c.138_162+20del](/variant/amn-c-138-162-plus-20del), [AMN c.208-13_211del](/variant/amn-c-208-minus-13-211del), [AMN p.Gly5fs](/variant/amn-p-gly5fs), [AMN p.Gln12fs](/variant/amn-p-gln12fs), [AMN p.Gly170fs](/variant/amn-p-gly170fs), [AMN p.Pro381fs](/variant/amn-p-pro381fs), [AMN p.Pro42fs](/variant/amn-p-pro42fs), [AMN c.1006+11_1008del](/variant/amn-c-1006-plus-11-1008del).

### 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 4855611). 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.*