# NM_000618.5(IGF1):c.402+1663C>A

https://sugi.bio/variant/igf1-c-402-plus-1663c-a

## Summary

**IGF1 c.402+1663C>A** is classified **Likely benign** in IGF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0925); Low-frequency (popmax 2.99%, afr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs6213 · 3 submitters · AlphaMissense likely benign · low-frequency (popmax 2.99%, afr)

## For patients & families {#patients}

This is a change in the IGF1 gene that is classified as likely benign — not considered disease-causing, 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 | [IGF1](https://sugi.bio/atlas/gene/IGF1/) |
| Coding change (HGVS c.) | c.402+1663C>A |
| MANE Select transcript | [NM_000618](https://www.ncbi.nlm.nih.gov/nuccore/NM_000618) |
| dbSNP | [rs6213](https://www.ncbi.nlm.nih.gov/snp/rs6213/) |
| Variant type | single nucleotide variant |
| Location | chr12:102417846-102417846 (GRCh38) |
| ClinVar | [VCV376935](https://www.ncbi.nlm.nih.gov/clinvar/variation/376935/) |

**All HGVS expressions:** `NC_000012.11:g.102811624G>T`, `NC_000012.12:g.102417846G>T`, `NG_011713.1:g.67755C>A`, `NM_000618.5:c.402+1663C>A`, `NM_001111283.3:c.451+109C>A`, `NM_001111284.2:c.354+1663C>A`, `NM_001111285.3:c.560C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0925)
- REVEL 0.319 (indeterminate)
- SaProt LLR -7.459 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 2.011, GERP -1.47, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.26**. 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.*
- Splice region: **deep intronic (+1663 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 0.17**, o/e 0.99 (1 kb window 102,417,000–102,418,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for IGF1 (305 scored positions, the nearest 12 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **2.99%** (afr) · FAF95 2.89% · FAF99 2.85% · 2,241/74,938 in the highest group · 2,633/1,613,700 alleles overall — low-frequency (popmax 2.99%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.99% | 33 |
| Middle Eastern | 0.396% | 253 |
| Remaining individuals (not grpmax-eligible) | 0.219% | 456 |
| Admixed American | 0.143% | 698 |
| European (non-Finnish) | 0.0119% | 8,427 |
| South Asian | 0.00549% | 18,208 |

*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}

**IGF1** population constraint: LOEUF 0.675, pLI 0.75933, missense-Z 2.1757. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 59.69, 0% of residues very-high.

**32 experimental structure(s)** (PDB): [1B9G](https://www.rcsb.org/structure/1B9G), [1BQT](https://www.rcsb.org/structure/1BQT), [1GZR](https://www.rcsb.org/structure/1GZR), [1GZY](https://www.rcsb.org/structure/1GZY), [1GZZ](https://www.rcsb.org/structure/1GZZ), [1H02](https://www.rcsb.org/structure/1H02) — incl. mutant structure 8EYR.

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

*Describes the biological roles of IGF1 (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:** IGF1's established molecular role includes insulin receptor binding.


### Pathways affected {#pathways}

IGF1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Synthesis, secretion, and deacylation of Ghrelin](https://reactome.org/content/detail/R-HSA-422085) | curated |

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

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

**Biological process:** cell activation, cell population proliferation, positive regulation of cell population proliferation, insulin receptor signaling pathway, response to heat, regulation of gene expression.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-18.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Likely benign | criteria provided, single submitter | clinical testing | 2017-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-18 |

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

## Similar variants {#similar}

Related IGF1 variant pages (same residue, condition, or type): [IGF1 c.*260A>T](/variant/igf1-c-star-260a-t), [IGF1 p.Ala115Val](/variant/igf1-p-ala115val), [IGF1 p.Arg119His](/variant/igf1-p-arg119his), [IGF1 p.Arg122His](/variant/igf1-p-arg122his), [IGF1 p.Cys54Trp](/variant/igf1-p-cys54trp), [IGF1 p.Leu7Phe](/variant/igf1-p-leu7phe), [IGF1 c.*105T>C](/variant/igf1-c-star-105t-c), [IGF1 c.*1770C>T](/variant/igf1-c-star-1770c-t).

### 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 376935). 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.*