# NM_016247.4(IMPG2):c.255dup (p.Pro86fs)

https://sugi.bio/variant/impg2-p-pro86fs

## Summary

**IMPG2 p.Pro86fs (c.255dup)** is classified **Pathogenic** in IMPG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2107148760 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the IMPG2 gene that is reported as disease-causing, but on limited review, 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 | [IMPG2](https://sugi.bio/atlas/gene/IMPG2/) |
| Protein change (HGVS p.) | p.Pro86fs |
| Coding change (HGVS c.) | c.255dup |
| MANE Select transcript | [NM_016247](https://www.ncbi.nlm.nih.gov/nuccore/NM_016247) |
| dbSNP | [rs2107148760](https://www.ncbi.nlm.nih.gov/snp/rs2107148760/) |
| Variant type | Duplication |
| Location | chr3:101319662-101319663 (GRCh38) |
| ClinVar | [VCV1406029](https://www.ncbi.nlm.nih.gov/clinvar/variation/1406029/) |

**All HGVS expressions:** `NC_000003.11:g.101038509dup`, `NC_000003.12:g.101319665dup`, `NG_028284.1:g.5913dup`, `NM_016247.4:c.255dup`

## 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 5.935, GERP 1.6, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.773, pLI 7.7387e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 19**, so the transcript is predicted to undergo NMD.
- 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**IMPG2** population constraint: LOEUF 0.773, pLI 7.7387e-15, missense-Z 0.94914. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **IMPG2-related recessive retinopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 54.28, 12% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-22 |

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

## Similar variants {#similar}

Related IMPG2 variant pages (same residue, condition, or type): [IMPG2 p.Pro86Thr](/variant/impg2-p-pro86thr), [IMPG2 c.3023-6_3030dup](/variant/impg2-c-3023-minus-6-3030dup), [IMPG2 p.Asp23fs](/variant/impg2-p-asp23fs), [IMPG2 p.Cys1077fs](/variant/impg2-p-cys1077fs), [IMPG2 p.Gln607fs](/variant/impg2-p-gln607fs), [IMPG2 p.Glu757fs](/variant/impg2-p-glu757fs), [IMPG2 p.Leu367fs](/variant/impg2-p-leu367fs), [IMPG2 c.1240-9dup](/variant/impg2-c-1240-minus-9dup).

### 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 1406029). 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.*