# NM_178497.5(ODAPH):c.225dup (p.Pro76fs)

https://sugi.bio/variant/odaph-p-pro76fs

## Summary

**ODAPH p.Pro76fs (c.225dup)** is classified **Likely pathogenic** in ODAPH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-21). Associated with amelogenesis imperfecta hypomaturation type 2A4.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the ODAPH gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to amelogenesis imperfecta hypomaturation type 2A4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015847/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ODAPH](https://sugi.bio/atlas/gene/ODAPH/) |
| Protein change (HGVS p.) | p.Pro76fs |
| Coding change (HGVS c.) | c.225dup |
| MANE Select transcript | [NM_178497](https://www.ncbi.nlm.nih.gov/nuccore/NM_178497) |
| Variant type | Duplication |
| Location | chr4:75564264-75564265 (GRCh38) |
| ClinVar | [VCV4813733](https://www.ncbi.nlm.nih.gov/clinvar/variation/4813733/) |

**All HGVS expressions:** `NC_000004.11:g.76489481dup`, `NC_000004.12:g.75564271dup`, `NG_032974.1:g.13224dup`, `NM_001206981.2:c.269dup`, `NM_001257072.2:c.206+19dup`, `NM_178497.5:c.225dup`

## 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 -0.025, GERP -5.03 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.704, pLI 0.071659. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**ODAPH** population constraint: LOEUF 1.704, pLI 0.071659, missense-Z 0.3853. *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 61.64, 5% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-21 |

## Associated conditions {#conditions}

[amelogenesis imperfecta hypomaturation type 2A4](https://sugi.bio/atlas/disease/amelogenesis-imperfecta-hypomaturation-type-2a4/).

**Reported phenotype names (ClinVar):** Amelogenesis imperfecta hypomaturation type 2A4, Amelogenesis imperfecta, hypomaturation type, IIA4.

## Similar variants {#similar}

Related ODAPH variant pages (same residue, condition, or type): [C4orf26 c.318G>A](/variant/c4orf26-c-318g-a), [ODAPH p.Arg77Ter](/variant/odaph-p-arg77ter), [ODAPH p.Val18fs](/variant/odaph-p-val18fs), [ODAPH c.68-2A>T](/variant/odaph-c-68-minus-2a-t), [ODAPH p.Cys43Ter](/variant/odaph-p-cys43ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4813733). 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.*