# NM_000207.3(INS):c.63A>G (p.Pro21=)

https://sugi.bio/variant/ins-p-pro21

## Summary

**INS p.Pro21= (c.63A>G)** is classified **Conflicting classifications of pathogenicity** in INS (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-24). Low-frequency (popmax 1.72%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs11564720 · 7 submitters · 2 linked conditions · low-frequency (popmax 1.72%, afr)

## For patients & families {#patients}

This is a change in the INS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Inborn genetic diseases.

*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 | [INS](https://sugi.bio/atlas/gene/INS/) |
| Protein change (HGVS p.) | p.Pro21= |
| Coding change (HGVS c.) | c.63A>G |
| MANE Select transcript | [NM_000207](https://www.ncbi.nlm.nih.gov/nuccore/NM_000207) |
| dbSNP | [rs11564720](https://www.ncbi.nlm.nih.gov/snp/rs11564720/) |
| Variant type | single nucleotide variant |
| Location | chr11:2160909-2160909 (GRCh38) |
| ClinVar | [VCV255533](https://www.ncbi.nlm.nih.gov/clinvar/variation/255533/) |

**All HGVS expressions:** `NC_000011.10:g.2160909T>C`, `NC_000011.9:g.2182139T>C`, `NG_007114.1:g.5286A>G`, `NG_050578.1:g.5301A>G`, `NM_000207.3:c.63A>G`, `NM_001042376.3:c.63A>G`, `NM_001185097.2:c.63A>G`, `NM_001185098.2:c.63A>G`, `NM_001291897.2:c.63A>G`, `NR_003512.4:n.122A>G`

## 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 -20, GERP -2.04 — fast-evolving / accelerated position
- CADD: **PHRED 0.011**. 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 **1.72%** (afr) · FAF95 1.64% · FAF99 1.61% · 1,288/75,048 in the highest group · 1,786/1,612,630 alleles overall — low-frequency (popmax 1.72%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.72% | 58 |
| Remaining individuals (not grpmax-eligible) | 0.173% | 578 |
| Middle Eastern | 0.165% | 606 |
| Admixed American | 0.143% | 698 |
| European (non-Finnish) | 0.0242% | 4,125 |
| South Asian | 0.00439% | 22,770 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,588 |
| Finnish (not grpmax-eligible) | 0.00319% | 31,374 |
| East Asian | 0.00223% | 44,876 |

*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}

**INS** population constraint: LOEUF 1.195, pLI 0.019816, missense-Z 0.85977; 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):

- **monogenic diabetes** — Definitive (AR)
- **monogenic diabetes** — Definitive (AD)

## Protein context {#protein}

Residue **21** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 53.19, 0% of residues very-high.

**386 experimental structure(s)** (PDB): [1A7F](https://www.rcsb.org/structure/1A7F), [1AI0](https://www.rcsb.org/structure/1AI0), [1AIY](https://www.rcsb.org/structure/1AIY), [1B9E](https://www.rcsb.org/structure/1B9E), [1BEN](https://www.rcsb.org/structure/1BEN), [1EFE](https://www.rcsb.org/structure/1EFE) — incl. mutant structure 1A7F.

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

*Describes the biological roles of INS (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:** INS's established molecular role includes protease binding.


### Pathways affected {#pathways}

INS participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [IRS activation](https://reactome.org/content/detail/R-HSA-74713) | curated |
| [Insulin receptor recycling](https://reactome.org/content/detail/R-HSA-77387) | curated |
| [Insulin receptor signalling cascade](https://reactome.org/content/detail/R-HSA-74751) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [Signal attenuation](https://reactome.org/content/detail/R-HSA-74749) | curated |
| [Signaling by Insulin receptor](https://reactome.org/content/detail/R-HSA-74752) | curated |
| [Synthesis, secretion, and deacylation of Ghrelin](https://reactome.org/content/detail/R-HSA-422085) | curated |
| [FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes](https://reactome.org/content/detail/R-HSA-9615017) | electronic |
| [Insulin processing](https://reactome.org/content/detail/R-HSA-264876) | electronic |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | electronic |
| [Regulation of gene expression in beta cells](https://reactome.org/content/detail/R-HSA-210745) | electronic |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | electronic |

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

**Molecular function:** protease binding, insulin receptor binding, insulin-like growth factor receptor binding, hormone activity, identical protein binding, receptor ligand activity.

**Biological process:** positive regulation of cytokine production, negative regulation of acute inflammatory response, acute-phase response, G protein-coupled receptor signaling pathway, positive regulation of cell population proliferation, insulin receptor signaling pathway.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-24.

**Submitter consensus:** conflicting (4 Benign, 2 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-07-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-07 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Uncertain significance | criteria provided, single submitter | research |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-24 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [maturity-onset diabetes of the young type 10](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young-type-10/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, not provided, Maturity-onset diabetes of the young type 10, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related INS variant pages (same residue, condition, or type): [INS c.-152C>A](/variant/ins-c-minus-152c-a), [INS c.-152C>G](/variant/ins-c-minus-152c-g), [INS p.Arg89His](/variant/ins-p-arg89his), [INS p.Met1Val](/variant/ins-p-met1val), [INS p.Val42Ala](/variant/ins-p-val42ala), [INS c.187+3G>A](/variant/ins-c-187-plus-3g-a), [INS c.-152C>T](/variant/ins-c-minus-152c-t), [INS p.Ala12Val](/variant/ins-p-ala12val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 255533). 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.*