# NM_152424.4(AMER1):c.370C>T (p.Pro124Ser)

https://sugi.bio/variant/amer1-p-pro124ser

## Summary

**AMER1 p.Pro124Ser (c.370C>T)** is classified **Uncertain significance** in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-10). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.023%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1602068444 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.023%, mid)

## For patients & families {#patients}

This is a change in the AMER1 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 | [AMER1](https://sugi.bio/atlas/gene/AMER1/) |
| Protein change (HGVS p.) | p.Pro124Ser |
| Coding change (HGVS c.) | c.370C>T |
| MANE Select transcript | [NM_152424](https://www.ncbi.nlm.nih.gov/nuccore/NM_152424) |
| dbSNP | [rs1602068444](https://www.ncbi.nlm.nih.gov/snp/rs1602068444/) |
| Variant type | single nucleotide variant |
| Location | chrX:64192917-64192917 (GRCh38) |
| ClinVar | [VCV2822239](https://www.ncbi.nlm.nih.gov/clinvar/variation/2822239/) |

**All HGVS expressions:** `LRG_1259:g.17828C>T`, `LRG_1259t1:c.370C>T`, `NC_000023.10:g.63412797G>A`, `NC_000023.11:g.64192917G>A`, `NG_021345.1:g.17828C>T`, `NM_152424.4:c.370C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0729)
- REVEL 0.072 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.271 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.781, GERP 0.803, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 7.951**. 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 1.07** across the covering region of the MANE Select transcript (64,189,882–64,193,286), spanning 3,404 bp. Chi-square p 0.037. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.023%** (mid) · 1/4,355 in the highest group · 1/111,894 alleles overall — ultra-rare (popmax 0.023%, mid).

*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}


Curated gene–disease validity (ClinGen):

- **osteopathia striata with cranial sclerosis** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 48.88, 8% of residues very-high.

**3 experimental structure(s)** (PDB): [4YJE](https://www.rcsb.org/structure/4YJE), [4YJL](https://www.rcsb.org/structure/4YJL), [4YK6](https://www.rcsb.org/structure/4YK6).

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

*Describes the biological roles of AMER1 (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:** AMER1's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding. In Reactome, AMER1 is annotated in disease pathway(s) including **APC truncation mutants have impaired AXIN binding**, **AXIN missense mutants destabilize the destruction complex**.

**Disease mechanism (Reactome):** AMER1 loss or alteration is curated in [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337), [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340), [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747).

### Pathways affected {#pathways}

AMER1 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337) | curated |
| ⚕ [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340) | curated |
| ⚕ [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747) | curated |
| ⚕ [CTNNB1 S37 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358749) | curated |
| ⚕ [CTNNB1 S45 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358751) | curated |
| ⚕ [CTNNB1 T41 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358752) | curated |
| ⚕ [Signaling by GSK3beta mutants](https://reactome.org/content/detail/R-HSA-5339716) | curated |
| ⚕ [Truncations of AMER1 destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467348) | curated |
| [Beta-catenin phosphorylation cascade](https://reactome.org/content/detail/R-HSA-196299) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |

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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, beta-catenin binding, beta-catenin destruction complex binding.

**Biological process:** positive regulation of protein ubiquitination, positive regulation of protein catabolic process, regulation of canonical Wnt signaling pathway, negative regulation of canonical Wnt signaling pathway, positive regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related AMER1 variant pages (same residue, condition, or type): [AMER1 p.Arg353Ter](/variant/amer1-p-arg353ter), [AMER1 p.Arg358Ter](/variant/amer1-p-arg358ter), [AMER1 p.Arg497Ter](/variant/amer1-p-arg497ter), [AMER1 p.Gln189Ter](/variant/amer1-p-gln189ter), [AMER1 p.Gln335Ter](/variant/amer1-p-gln335ter), [AMER1 p.Glu191Ter](/variant/amer1-p-glu191ter), [AMER1 p.Ala202Gly](/variant/amer1-p-ala202gly), [AMER1 p.Ala229Pro](/variant/amer1-p-ala229pro).

### 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 2822239). 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.*