# NM_016247.4(IMPG2):c.831T>C (p.Val277=)

https://sugi.bio/variant/impg2-p-val277

## Summary

**IMPG2 p.Val277= (c.831T>C)** is classified **Likely benign** in IMPG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-23). Very rare (popmax 0.00211%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00211%, nfe)

## For patients & families {#patients}

This is a change in the IMPG2 gene that is classified as likely benign — not considered disease-causing, 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.Val277= |
| Coding change (HGVS c.) | c.831T>C |
| MANE Select transcript | [NM_016247](https://www.ncbi.nlm.nih.gov/nuccore/NM_016247) |
| Variant type | single nucleotide variant |
| Location | chr3:101269571-101269571 (GRCh38) |
| ClinVar | [VCV4963560](https://www.ncbi.nlm.nih.gov/clinvar/variation/4963560/) |

**All HGVS expressions:** `NC_000003.11:g.100988415A>G`, `NC_000003.12:g.101269571A>G`, `NG_028284.1:g.56005T>C`, `NM_016247.4:c.831T>C`

## 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 2.216, GERP -2.62, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.24**. 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 (A>T, Δ0.29 acceptor loss), 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 **0.00211%** (nfe) · FAF95 0.00142% · FAF99 0.0012% · 24/1,139,662 in the highest group · 26/1,569,346 alleles overall — very rare (popmax 0.00211%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00328% | 30,513 |
| European (non-Finnish) (grpmax) | 0.00211% | 47,486 |

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 **277** lies in a UniProt-annotated variant site (in rp56); a UniProt-annotated variant site (in vmd5); the sea 1 domain.

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-23 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related IMPG2 variant pages (same residue, condition, or type): [IMPG2 p.Val277Ile](/variant/impg2-p-val277ile), [IMPG2 p.Val277Phe](/variant/impg2-p-val277phe), [IMPG2 c.1240-1G>A](/variant/impg2-c-1240-minus-1g-a), [IMPG2 c.1240-2A>G](/variant/impg2-c-1240-minus-2a-g), [IMPG2 c.502-2A>G](/variant/impg2-c-502-minus-2a-g), [IMPG2 c.583+1G>C](/variant/impg2-c-583-plus-1g-c), [IMPG2 c.667-1G>A](/variant/impg2-c-667-minus-1g-a), [IMPG2 c.828+1G>A](/variant/impg2-c-828-plus-1g-a).

### 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 4963560). 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.*