# NM_001113402.2(AMN1):c.17G>C (p.Arg6Pro)

https://sugi.bio/variant/amn1-p-arg6pro

## Summary

**AMN1 p.Arg6Pro (c.17G>C)** is classified **Uncertain significance** in AMN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely benign (0.1369); Very rare (popmax 0.00137%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00137%, afr)

## For patients & families {#patients}

This is a change in the AMN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [AMN1](https://sugi.bio/atlas/gene/AMN1/) |
| Protein change (HGVS p.) | p.Arg6Pro |
| Coding change (HGVS c.) | c.17G>C |
| MANE Select transcript | [NM_001113402](https://www.ncbi.nlm.nih.gov/nuccore/NM_001113402) |
| Variant type | single nucleotide variant |
| Location | chr12:31728992-31728992 (GRCh38) |
| ClinVar | [VCV3536029](https://www.ncbi.nlm.nih.gov/clinvar/variation/3536029/) |

**All HGVS expressions:** `NC_000012.11:g.31881926C>G`, `NC_000012.12:g.31728992C>G`, `NG_188258.1:g.153C>G`, `NM_001113402.2:c.17G>C`, `NM_001278411.2:c.-18G>C`, `NM_001278412.2:c.-247G>C`, `NR_103522.2:n.30G>C`, `NR_103523.1:n.183G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1369)
- REVEL 0.022 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.421 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.038, GERP -2.58, phastCons 0.497 — weakly conserved position
- CADD: **PHRED 15.09**. 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 0.80** across the covering region of the MANE Select transcript (31,672,307–31,729,008), spanning 56,701 bp. Chi-square p 0.00046. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.58 donor loss), 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 **0.00137%** (afr) · 1/73,036 in the highest group · 1/1,393,346 alleles overall — very rare (popmax 0.00137%, afr).

*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}

**AMN1** population constraint: LOEUF 0.838, pLI 0.0078309, missense-Z 1.5815. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.56, 76% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-02 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AMN1 variant pages (same residue, condition, or type): [AMN1 p.Ala109Ser](/variant/amn1-p-ala109ser), [AMN1 p.Arg223Pro](/variant/amn1-p-arg223pro), [AMN1 p.Arg3Cys](/variant/amn1-p-arg3cys), [AMN1 p.Arg5Gln](/variant/amn1-p-arg5gln), [AMN1 p.Arg69Leu](/variant/amn1-p-arg69leu), [AMN1 p.Arg85Gly](/variant/amn1-p-arg85gly), [AMN1 p.Asn206Ser](/variant/amn1-p-asn206ser), [AMN1 p.Asp72Asn](/variant/amn1-p-asp72asn).

### 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 3536029). 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.*