# NM_001142.2(AMELX):c.225G>A (p.Pro75=)

https://sugi.bio/variant/amelx-p-pro75

## Summary

**AMELX p.Pro75= (c.225G>A)** is classified **Likely benign** in AMELX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-06). Rare (popmax 0.119%, eas); Associated with AMELX-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs142884100 · 1 submitter · 1 linked condition · rare (popmax 0.119%, eas)

## For patients & families {#patients}

This is a change in the AMELX gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to AMELX-related disorder.

*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 | [AMELX](https://sugi.bio/atlas/gene/AMELX/) |
| Protein change (HGVS p.) | p.Pro75= |
| Coding change (HGVS c.) | c.225G>A |
| MANE Select transcript | [NM_001142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001142) |
| dbSNP | [rs142884100](https://www.ncbi.nlm.nih.gov/snp/rs142884100/) |
| Variant type | single nucleotide variant |
| Location | chrX:11298628-11298628 (GRCh38) |
| ClinVar | [VCV3051823](https://www.ncbi.nlm.nih.gov/clinvar/variation/3051823/) |

**All HGVS expressions:** `NC_000023.10:g.11316748G>A`, `NC_000023.11:g.11298628G>A`, `NG_012040.2:g.10217G>A`, `NG_012494.2:g.372074C>T`, `NM_001142.2:c.225G>A`, `NM_001287242.2:c.49-43921C>T`, `NM_006125.3:c.589-43921C>T`, `NM_013427.3:c.589-43921C>T`, `NM_182680.1:c.267G>A`, `NM_182681.1:c.177G>A`

## 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 4.638, GERP -0.371, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.71**. 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 (G>T, Δ0.20 acceptor 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 **0.119%** (eas) · FAF95 0.0896% · FAF99 0.0794% · 40/33,696 in the highest group · 50/1,207,864 alleles overall — rare (popmax 0.119%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.119% | 842 |
| African / African-American | 0.00355% | 28,203 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,576 |
| European (non-Finnish) | 0.000782% | 127,819 |

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 59.51, 0% of residues very-high.

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

*Describes the biological roles of AMELX (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:** AMELX's established molecular role includes structural constituent of tooth enamel.


### Pathways affected {#pathways}

AMELX participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

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

**Molecular function:** structural constituent of tooth enamel.

**Biological process:** tooth mineralization, enamel mineralization.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-12-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-12-06 |

## Associated conditions {#conditions}

[AMELX-related disorder](https://sugi.bio/atlas/disease/amelx-related-disorder/).

**Reported phenotype names (ClinVar):** AMELX-related disorder, AMELX-related condition.

## Similar variants {#similar}

Related AMELX variant pages (same residue, condition, or type): [AMELX p.Pro75Leu](/variant/amelx-p-pro75leu), [AMELX p.Met1Ile](/variant/amelx-p-met1ile), [AMELX p.Pro56Thr](/variant/amelx-p-pro56thr), [AMELX c.103-1G>A](/variant/amelx-c-103-minus-1g-a), [AMELX p.Gln141Ter](/variant/amelx-p-gln141ter), [AMELX p.Pro122=](/variant/amelx-p-pro122), [AMELX c.103-111A>G](/variant/amelx-c-103-minus-111a-g), [AMELX c.54+65T>C](/variant/amelx-c-54-plus-65t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3051823). 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.*