# NM_000612.6(IGF2):c.306G>A (p.Pro102=)

https://sugi.bio/variant/igf2-p-pro102

## Summary

**IGF2 p.Pro102= (c.306G>A)** is classified **Uncertain significance** in IGF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-19). Very rare (popmax 0.00335%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs536204564 · 1 submitter · very rare (popmax 0.00335%, 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.Pro102= |
| Coding change (HGVS c.) | c.306G>A |
| MANE Select transcript | [NM_000612](https://www.ncbi.nlm.nih.gov/nuccore/NM_000612) |
| dbSNP | [rs536204564](https://www.ncbi.nlm.nih.gov/snp/rs536204564/) |
| Variant type | single nucleotide variant |
| Location | chr11:2133517-2133517 (GRCh38) |
| ClinVar | [VCV1977706](https://www.ncbi.nlm.nih.gov/clinvar/variation/1977706/) |

**All HGVS expressions:** `LRG_1031:g.21087G>A`, `LRG_1031t1:c.306G>A`, `LRG_1031t2:c.306G>A`, `LRG_1031t3:c.306G>A`, `LRG_1031t4:c.306G>A`, `LRG_1031t5:c.474G>A`, `NC_000011.10:g.2133517C>T`, `NC_000011.9:g.2154747C>T`, `NG_008849.1:g.21087G>A`, `NG_050578.1:g.32693G>A`, `NM_000612.6:c.306G>A`, `NM_001007139.6:c.306G>A`, `NM_001127598.3:c.474G>A`, `NM_001291861.3:c.306G>A`, `NM_001291862.3:c.306G>A`, `NR_003512.4:n.1020G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.463, GERP 0.814, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 23.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.45**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.40** (loss), gain 0.03 / loss 0.40. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00335%** (amr) · FAF95 0.000556% · FAF99 0.000211% · 2/59,638 in the highest group · 10/1,610,276 alleles overall — very rare (popmax 0.00335%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00335% | 29,819 |
| European (non-Finnish) | 0.000679% | 147,317 |

*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 **102** lies in a UniProt-annotated variant site (in srs3).

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.


### 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 2022-02-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-19 |

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

## Similar variants {#similar}

Related IGF2 variant pages (same residue, condition, or type): [IGF2 p.Pro102Leu](/variant/igf2-p-pro102leu), [IGF2 c.157+5G>A](/variant/igf2-c-157-plus-5g-a), [IGF2 p.Glu36Ter](/variant/igf2-p-glu36ter), [IGF2 p.Gly34Cys](/variant/igf2-p-gly34cys), [IGF2 p.Ser20Ter](/variant/igf2-p-ser20ter), [IGF2 p.Ala167Ser](/variant/igf2-p-ala167ser), [IGF2 p.Arg138Trp](/variant/igf2-p-arg138trp), [IGF2 p.Arg154Cys](/variant/igf2-p-arg154cys).

### 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 1977706). 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.*