# NM_000612.6(IGF2):c.518del (p.Pro173fs)

https://sugi.bio/variant/igf2-p-pro173fs

## Summary

**IGF2 p.Pro173fs (c.518del)** is classified **Uncertain significance** in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). Very rare (popmax 0.00609%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00609%, amr)

## For patients & families {#patients}

This is a change in the IGF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [IGF2](https://sugi.bio/atlas/gene/IGF2/) |
| Protein change (HGVS p.) | p.Pro173fs |
| Coding change (HGVS c.) | c.518del |
| MANE Select transcript | [NM_000612](https://www.ncbi.nlm.nih.gov/nuccore/NM_000612) |
| Variant type | Deletion |
| Location | chr11:2133012-2133012 (GRCh38) |
| ClinVar | [VCV3372485](https://www.ncbi.nlm.nih.gov/clinvar/variation/3372485/) |

**All HGVS expressions:** `LRG_1031:g.21592del`, `LRG_1031t1:c.518del`, `LRG_1031t2:c.518del`, `LRG_1031t3:c.518del`, `LRG_1031t4:c.518del`, `LRG_1031t5:c.686del`, `NC_000011.10:g.2133018del`, `NC_000011.9:g.2154248del`, `NG_008849.1:g.21592del`, `NG_050578.1:g.33198del`, `NM_000612.6:c.518del`, `NM_001007139.6:c.518del`, `NM_001127598.3:c.686del`, `NM_001291861.3:c.518del`, `NM_001291862.3:c.518del`, `NR_003512.4:n.1232del`

## 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 -1.948, GERP -1.41 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.496, pLI 0.96), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — 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 deletion 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 **0.00609%** (amr) · FAF95 0.00161% · FAF99 0.000848% · 3/49,284 in the highest group · 16/1,545,910 alleles overall — very rare (popmax 0.00609%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00609% | 16,428 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00382% | 26,178 |
| East Asian | 0.00235% | 42,564 |
| African / African-American | 0.00138% | 72,296 |
| European (non-Finnish) | 0.000873% | 114,612 |

*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}

**IGF2** population constraint: LOEUF 0.496, pLI 0.96, missense-Z 1.269; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **Silver-Russell syndrome 3** — Definitive (AD)

## Protein context {#protein}

Residue **173** lies in a UniProt-annotated variant site (in srs3); a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 58.95, 0% of residues very-high.

**16 experimental structure(s)** (PDB): [1IGL](https://www.rcsb.org/structure/1IGL), [2L29](https://www.rcsb.org/structure/2L29), [2V5P](https://www.rcsb.org/structure/2V5P), [3E4Z](https://www.rcsb.org/structure/3E4Z), [3KR3](https://www.rcsb.org/structure/3KR3), [5L3L](https://www.rcsb.org/structure/5L3L) — incl. mutant structure 2L29.

## What this gene does {#gene-function}

*Describes the biological roles of IGF2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** IGF2's established molecular role includes insulin receptor binding. p.Pro173fs falls in the disordered region.


### Pathways affected {#pathways}

IGF2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |
| [IRS-related events triggered by IGF1R](https://reactome.org/content/detail/R-HSA-2428928) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [SHC-related events triggered by IGF1R](https://reactome.org/content/detail/R-HSA-2428933) | curated |
| [Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)](https://reactome.org/content/detail/R-HSA-2404192) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** insulin receptor binding, insulin-like growth factor receptor binding, integrin binding, growth factor activity.

**Biological process:** positive regulation of cell population proliferation, positive regulation of activated T cell proliferation, positive regulation of MAPK cascade, positive regulation of mitotic nuclear division, positive regulation of insulin receptor signaling pathway, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-12 |

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

## Similar variants {#similar}

Related IGF2 variant pages (same residue, condition, or type): [IGF2 p.Pro173Gln](/variant/igf2-p-pro173gln), [IGF2 p.Pro173Arg](/variant/igf2-p-pro173arg), [IGF2 p.Pro173Leu](/variant/igf2-p-pro173leu), [IGF2 p.Pro173Ser](/variant/igf2-p-pro173ser), [IGF2 p.Pro173=](/variant/igf2-p-pro173), [IGF2 p.Pro157_Leu158insTer](/variant/igf2-p-pro157-leu158inster), [IGF2 p.Arg61_Arg62insTer](/variant/igf2-p-arg61-arg62inster), [IGF2 p.Asp76fs](/variant/igf2-p-asp76fs).

### 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 3372485). 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.*