# NM_030943.4(AMN):c.492C>G (p.Arg164=)

https://sugi.bio/variant/amn-p-arg164

## Summary

**AMN p.Arg164= (c.492C>G)** is classified **Likely benign** in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Ultra-rare (popmax 0.0165%, mid); Associated with Imerslund-Grasbeck syndrome type 2.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1388154450 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the AMN gene that is classified as likely benign — not considered disease-causing, 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.Arg164= |
| Coding change (HGVS c.) | c.492C>G |
| MANE Select transcript | [NM_030943](https://www.ncbi.nlm.nih.gov/nuccore/NM_030943) |
| dbSNP | [rs1388154450](https://www.ncbi.nlm.nih.gov/snp/rs1388154450/) |
| Variant type | single nucleotide variant |
| Location | chr14:102928954-102928954 (GRCh38) |
| ClinVar | [VCV798651](https://www.ncbi.nlm.nih.gov/clinvar/variation/798651/) |

**All HGVS expressions:** `LRG_642:g.11299C>G`, `LRG_642t1:c.492C>G`, `NC_000014.8:g.103395291C>G`, `NC_000014.9:g.102928954C>G`, `NG_008276.2:g.11299C>G`, `NM_030943.4:c.492C>G`

## 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 1.023, GERP 0.049, phastCons 1 — weakly conserved position
- CADD: **PHRED 10.5**. 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 (C>T, Δ0.21 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 **0.0165%** (mid) · 1/6,076 in the highest group · 9/1,599,504 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,076 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,794 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **164** 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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-08-19.

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

**Submission history:** 2 submissions (2019–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-19 |

## 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, PERNICIOUS ANEMIA, JUVENILE, DUE TO SELECTIVE INTESTINAL MALABSORPTION OF VITAMIN B12, WITH PROTEINURIA, ENTEROCYTE COBALAMIN MALABSORPTION, ENTEROCYTE INTRINSIC FACTOR RECEPTOR, DEFECT OF, Imerslund-Gräsbeck syndrome, Megaloblastic anemia due to inborn errors of metabolism.

## Similar variants {#similar}

Related AMN variant pages (same residue, condition, or type): [AMN p.Arg164Gln](/variant/amn-p-arg164gln), [AMN p.Arg164His](/variant/amn-p-arg164his), [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).

### 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 798651). 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.*