# NM_004969.4(IDE):c.971A>G (p.Lys324Arg)

https://sugi.bio/variant/ide-p-lys324arg

## Summary

**IDE p.Lys324Arg (c.971A>G)** is classified **Uncertain significance** in IDE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.093); Ultra-rare (popmax 0.0286%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs572543538 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0286%, sas)

## For patients & families {#patients}

This is a change in the IDE 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 | [IDE](https://sugi.bio/atlas/gene/IDE/) |
| Protein change (HGVS p.) | p.Lys324Arg |
| Coding change (HGVS c.) | c.971A>G |
| MANE Select transcript | [NM_004969](https://www.ncbi.nlm.nih.gov/nuccore/NM_004969) |
| dbSNP | [rs572543538](https://www.ncbi.nlm.nih.gov/snp/rs572543538/) |
| Variant type | single nucleotide variant |
| Location | chr10:92508817-92508817 (GRCh38) |
| ClinVar | [VCV3108017](https://www.ncbi.nlm.nih.gov/clinvar/variation/3108017/) |

**All HGVS expressions:** `NC_000010.10:g.94268574T>C`, `NC_000010.11:g.92508817T>C`, `NG_013012.1:g.70279A>G`, `NM_001322793.2:c.971A>G`, `NM_001322794.2:c.854A>G`, `NM_001322795.2:c.848A>G`, `NM_001322796.1:c.848A>G`, `NM_001410974.1:c.848A>G`, `NM_004969.4:c.971A>G`, `NR_136399.2:n.1045A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.093)
- REVEL 0.097 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.3 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.017, GERP 2.03, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.1**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (92,454,447–92,510,088), spanning 55,641 bp. Chi-square p 4.3e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.28 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0286%** (sas) · FAF95 0.0199% · FAF99 0.0171% · 26/91,058 in the highest group · 26/1,613,152 alleles overall — ultra-rare (popmax 0.0286%, sas).

*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}

**IDE** population constraint: LOEUF 0.638, pLI 0.076756, missense-Z 2.1505. *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 **324** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.06, 93% of residues very-high.

**62 experimental structure(s)** (PDB): [2G47](https://www.rcsb.org/structure/2G47), [2G48](https://www.rcsb.org/structure/2G48), [2G49](https://www.rcsb.org/structure/2G49), [2G54](https://www.rcsb.org/structure/2G54), [2G56](https://www.rcsb.org/structure/2G56), [2JBU](https://www.rcsb.org/structure/2JBU).

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

*Describes the biological roles of IDE (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:** IDE's established molecular role includes endopeptidase activity.


### Pathways affected {#pathways}

IDE participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Insulin receptor recycling](https://reactome.org/content/detail/R-HSA-77387) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** endopeptidase activity, metalloendopeptidase activity, ATP binding, zinc ion binding, peptide binding, identical protein binding.

**Biological process:** proteolysis, bradykinin catabolic process, ubiquitin recycling, antigen processing and presentation of endogenous peptide antigen via MHC class I, protein catabolic process, positive regulation of protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-13 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related IDE variant pages (same residue, condition, or type): [IDE p.Asn841=](/variant/ide-p-asn841), [IDE p.His10=](/variant/ide-p-his10), [IDE p.Ile791=](/variant/ide-p-ile791), [IDE p.Ala185Glu](/variant/ide-p-ala185glu), [IDE p.Ala452Thr](/variant/ide-p-ala452thr), [IDE p.Ala479Thr](/variant/ide-p-ala479thr), [IDE p.Ala544Val](/variant/ide-p-ala544val), [IDE p.Ala610Val](/variant/ide-p-ala610val).

### 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 3108017). 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.*