# NM_000618.5(IGF1):c.150G>A (p.Pro50=)

https://sugi.bio/variant/igf1-p-pro50

## Summary

**IGF1 p.Pro50= (c.150G>A)** is classified **Conflicting classifications of pathogenicity** in IGF1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0171%, nfe); Associated with growth delay due to insulin-like growth factor type 1 deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs373202198 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0171%, nfe)

## For patients & families {#patients}

This is a change in the IGF1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to growth delay due to insulin-like growth factor type 1 deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | IGF1 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Growth delay due to insulin-like growth factor type 1 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Very frequent (99-80%)
- Prelingual sensorineural hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Short attention span — Very frequent (99-80%)
- Hyperactivity — Very frequent (99-80%)
- Insulin resistance — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010627/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IGF1](https://sugi.bio/atlas/gene/IGF1/) |
| Protein change (HGVS p.) | p.Pro50= |
| Coding change (HGVS c.) | c.150G>A |
| MANE Select transcript | [NM_000618](https://www.ncbi.nlm.nih.gov/nuccore/NM_000618) |
| dbSNP | [rs373202198](https://www.ncbi.nlm.nih.gov/snp/rs373202198/) |
| Variant type | single nucleotide variant |
| Location | chr12:102475713-102475713 (GRCh38) |
| ClinVar | [VCV880615](https://www.ncbi.nlm.nih.gov/clinvar/variation/880615/) |

**All HGVS expressions:** `NC_000012.11:g.102869491C>T`, `NC_000012.12:g.102475713C>T`, `NG_011713.1:g.9888G>A`, `NM_000618.5:c.150G>A`, `NM_001111283.3:c.150G>A`, `NM_001111284.2:c.102G>A`, `NM_001111285.3:c.150G>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 (below), not from a missing predictor score.
- Conservation: phyloP -15.051, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 0.386**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0171%** (nfe) · FAF95 0.0152% · FAF99 0.0144% · 202/1,180,048 in the highest group · 215/1,614,086 alleles overall — ultra-rare (popmax 0.0171%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0171% | 5,842 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| Admixed American | 0.005% | 20,003 |
| East Asian | 0.00446% | 22,446 |
| African / African-American | 0.004% | 24,975 |
| South Asian | 0.0011% | 91,084 |

*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}

Residue **50** lies in the 'b' region.

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. p.Pro50= falls in the b region.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-01.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-03 |

## Associated conditions {#conditions}

[growth delay due to insulin-like growth factor type 1 deficiency](https://sugi.bio/atlas/disease/growth-delay-due-to-insulin-like-growth-factor-type-1-deficiency/).

**Reported phenotype names (ClinVar):** Growth delay due to insulin-like growth factor type 1 deficiency, not provided, not specified, AllHighlyPenetrant, GROWTH RETARDATION WITH SENSORINEURAL DEAFNESS AND MENTAL RETARDATION, IGF1 DEFICIENCY, 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 c.*105T>C](/variant/igf1-c-star-105t-c), [IGF1 c.*1770C>T](/variant/igf1-c-star-1770c-t), [IGF1 c.*2364A>G](/variant/igf1-c-star-2364a-g), [IGF1 c.*259A>T](/variant/igf1-c-star-259a-t), [IGF1 c.*261A>T](/variant/igf1-c-star-261a-t), [IGF1 c.*263T>A](/variant/igf1-c-star-263t-a), [IGF1 c.*3226C>G](/variant/igf1-c-star-3226c-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 880615). 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.*