# NM_016247.4(IMPG2):c.3706CAA[1] (p.Gln1237del)

https://sugi.bio/variant/impg2-p-gln1237del

## Summary

**IMPG2 p.Gln1237del (c.3706CAA[1])** is classified **Uncertain significance** in IMPG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). Very rare (popmax 0.0056%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs759574080 · 3 submitters · very rare (popmax 0.0056%, nfe)

## For patients & families {#patients}

This is a change in the IMPG2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters.

*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.Gln1237del |
| Coding change (HGVS c.) | c.3706CAA[1] |
| MANE Select transcript | [NM_016247](https://www.ncbi.nlm.nih.gov/nuccore/NM_016247) |
| dbSNP | [rs759574080](https://www.ncbi.nlm.nih.gov/snp/rs759574080/) |
| Variant type | Microsatellite |
| Location | chr3:101228799-101228801 (GRCh38) |
| ClinVar | [VCV1002947](https://www.ncbi.nlm.nih.gov/clinvar/variation/1002947/) |

**All HGVS expressions:** `NC_000003.11:g.100947643TTG[1]`, `NC_000003.12:g.101228799TTG[1]`, `NG_028284.1:g.96772CAA[1]`, `NM_016247.4:c.3706CAA[1]`

## 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 3.395, GERP -1.03, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 12.79**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0056%** (nfe) · FAF95 0.00451% · FAF99 0.00412% · 66/1,179,388 in the highest group · 76/1,613,284 alleles overall — very rare (popmax 0.0056%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,923 |
| European (non-Finnish) (grpmax) | 0.0056% | 17,870 |
| South Asian | 0.0022% | 45,534 |
| African / African-American | 0.00134% | 74,890 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **1237** lies in a UniProt-annotated variant site (in rp56); a UniProt-annotated variant site (in vmd5).

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

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-01.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-23 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-01 |

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

## Similar variants {#similar}

Related IMPG2 variant pages (same residue, condition, or type): [IMPG2 p.Leu1053_Cys1054insTer](/variant/impg2-p-leu1053-cys1054inster), [IMPG2 p.Ser527fs](/variant/impg2-p-ser527fs), [IMPG2 p.Pro434del](/variant/impg2-p-pro434del), [IMPG2 p.Arg782fs](/variant/impg2-p-arg782fs), [IMPG2 p.Glu1033fs](/variant/impg2-p-glu1033fs), [IMPG2 c.3423-7_3423-4del](/variant/impg2-c-3423-minus-7-3423-minus-4del), [IMPG2 p.Asn415del](/variant/impg2-p-asn415del), [IMPG2 p.Glu272del](/variant/impg2-p-glu272del).

### 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 1002947). 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.*