# NM_030943.4(AMN):c.928G>A (p.Val310Met)

https://sugi.bio/variant/amn-p-val310met

## Summary

**AMN p.Val310Met (c.928G>A)** is classified **Uncertain significance** in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-30). AlphaMissense: ambiguous (0.4536); Rare (popmax 0.121%, afr); Associated with Imerslund-Grasbeck syndrome type 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs201788173 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · rare (popmax 0.121%, afr)

## For patients & families {#patients}

This is a change in the AMN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Val310Met |
| Coding change (HGVS c.) | c.928G>A |
| MANE Select transcript | [NM_030943](https://www.ncbi.nlm.nih.gov/nuccore/NM_030943) |
| dbSNP | [rs201788173](https://www.ncbi.nlm.nih.gov/snp/rs201788173/) |
| Variant type | single nucleotide variant |
| Location | chr14:102930008-102930008 (GRCh38) |
| ClinVar | [VCV1419551](https://www.ncbi.nlm.nih.gov/clinvar/variation/1419551/) |

**All HGVS expressions:** `LRG_642:g.12353G>A`, `NC_000014.8:g.103396345G>A`, `NC_000014.9:g.102930008G>A`, `NG_008276.2:g.12353G>A`, `NM_030943.4:c.928G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4536) — no call either way
- REVEL 0.669 (pathogenic-leaning)
- SaProt LLR -7.605 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- SpliceAI predicts **donor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.632, GERP 0.959, phastCons 1 — highly conserved
- CADD: **PHRED 27.7**. 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 1.06** across the covering region of the MANE Select transcript (102,922,689–102,930,677), spanning 7,988 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.25**.
- Population frequency (gnomAD v4.1): grpmax **0.121%** (afr) · FAF95 0.101% · FAF99 0.0932% · 89/73,494 in the highest group · 95/1,559,010 alleles overall — rare (popmax 0.121%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.121% | 826 |
| Admixed American | 0.00763% | 13,103 |
| East Asian | 0.00242% | 41,402 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,390 |

*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 **310** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-30.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-09 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-30 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome, Megaloblastic anemia 1, Norwegian type, MEGALOBLASTIC ANEMIA, NORWEGIAN TYPE, Imerslund-Gräsbeck syndrome 2, Imerslund-Gräsbeck syndrome, Megaloblastic anemia due to inborn errors of metabolism, ENTEROCYTE COBALAMIN MALABSORPTION, ENTEROCYTE INTRINSIC FACTOR RECEPTOR, DEFECT OF, PERNICIOUS ANEMIA, JUVENILE, DUE TO SELECTIVE INTESTINAL MALABSORPTION OF VITAMIN B12, WITH PROTEINURIA.

## Similar variants {#similar}

Related AMN variant pages (same residue, condition, or type): [AMN c.208-1G>C](/variant/amn-c-208-minus-1g-c), [AMN c.296-1G>A](/variant/amn-c-296-minus-1g-a), [AMN c.44-1G>A](/variant/amn-c-44-minus-1g-a), [AMN c.760+1G>A](/variant/amn-c-760-plus-1g-a), [AMN c.844-1G>C](/variant/amn-c-844-minus-1g-c), [AMN p.Thr41Ile](/variant/amn-p-thr41ile), [AMN p.Trp391Ter](/variant/amn-p-trp391ter), [AMN c.296-3C>T](/variant/amn-c-296-minus-3c-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 1419551). 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.*