# NM_012064.4(MIP):c.658_661dup (p.Phe221Ter)

https://sugi.bio/variant/mip-p-phe221ter

## Summary

**MIP p.Phe221Ter (c.658_661dup)** is classified **Likely pathogenic** in MIP (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-10). Associated with MIP-related disorder.

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

## For patients & families {#patients}

This is a change in the MIP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to MIP-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 | [MIP](https://sugi.bio/atlas/gene/MIP/) |
| Protein change (HGVS p.) | p.Phe221Ter |
| Coding change (HGVS c.) | c.658_661dup |
| MANE Select transcript | [NM_012064](https://www.ncbi.nlm.nih.gov/nuccore/NM_012064) |
| Variant type | Duplication |
| Location | chr12:56451410-56451411 (GRCh38) |
| ClinVar | [VCV4917259](https://www.ncbi.nlm.nih.gov/clinvar/variation/4917259/) |

**All HGVS expressions:** `LRG_1291:g.22753_22756dup`, `LRG_1291t1:c.658_661dup`, `NC_000012.11:g.56845195_56845198dup`, `NC_000012.12:g.56451411_56451414dup`, `NG_021397.2:g.22753_22756dup`, `NM_012064.4:c.658_661dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 9.366, GERP 0.631, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.91, 47% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-10 |

## Associated conditions {#conditions}

[MIP-related disorder](https://sugi.bio/atlas/disease/mip-related-disorder/).

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

## Similar variants {#similar}

Related MIP variant pages (same residue, condition, or type): [MIP c.606+1G>C](/variant/mip-c-606-plus-1g-c), [MIP p.Leu143fs](/variant/mip-p-leu143fs), [MIP p.Leu222fs](/variant/mip-p-leu222fs), [MIP p.Trp202Ter](/variant/mip-p-trp202ter), [MIP p.Tyr219Ter](/variant/mip-p-tyr219ter), [MIP p.Leu55fs](/variant/mip-p-leu55fs), [MIP c.*1237_*1238dup](/variant/mip-c-star-1237-star-1238dup), [MIP c.*148dup](/variant/mip-c-star-148dup).

### 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 4917259). 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.*