# NM_006303.4(AIMP2):c.656_659del (p.Ser219fs)

https://sugi.bio/variant/aimp2-p-ser219fs

## Summary

**AIMP2 p.Ser219fs (c.656_659del)** is classified **Likely pathogenic** in AIMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-17). Ultra-rare (popmax 0.0147%, afr); Associated with leukodystrophy, hypomyelinating, 17.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs760123492 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0147%, afr)

## For patients & families {#patients}

This is a change in the AIMP2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to leukodystrophy, hypomyelinating, 17.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025980/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AIMP2](https://sugi.bio/atlas/gene/AIMP2/) |
| Protein change (HGVS p.) | p.Ser219fs |
| Coding change (HGVS c.) | c.656_659del |
| MANE Select transcript | [NM_006303](https://www.ncbi.nlm.nih.gov/nuccore/NM_006303) |
| dbSNP | [rs760123492](https://www.ncbi.nlm.nih.gov/snp/rs760123492/) |
| Variant type | Microsatellite |
| Location | chr7:6023381-6023384 (GRCh38) |
| ClinVar | [VCV3062023](https://www.ncbi.nlm.nih.gov/clinvar/variation/3062023/) |

**All HGVS expressions:** `NC_000007.13:g.6063013CT[1]`, `NC_000007.14:g.6023382CT[1]`, `NG_050738.1:g.19132CT[1]`, `NM_001134335.2:c.*1287GA[1]`, `NM_001326606.2:c.536_539del`, `NM_001326607.2:c.449_452del`, `NM_001326609.2:c.422_425del`, `NM_001326610.2:c.422_425del`, `NM_001326611.3:c.422_425del`, `NM_001362785.2:c.569_572del`, `NM_001362787.2:c.524_527del`, `NM_006303.4:c.656_659del`, `NM_014413.4:c.*1287GA[1]`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.937, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.107, pLI 2.3887e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 34.0**. 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** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0147%** (afr) · FAF95 0.00815% · FAF99 0.00633% · 11/74,942 in the highest group · 20/1,614,056 alleles overall — ultra-rare (popmax 0.0147%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0147% | 6,813 |
| East Asian | 0.00445% | 22,447 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,038 |
| European (non-Finnish) | 0.000508% | 196,672 |

*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}

**AIMP2** population constraint: LOEUF 1.107, pLI 2.3887e-06, missense-Z -1.4459. *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):

- **leukodystrophy, hypomyelinating, 17** — Definitive (AR)

## Protein context {#protein}

Residue **219** lies in the 'interaction with tp53' region; an α-helix; a UniProt-annotated variant site (in hld17).

AlphaFold model confidence (whole protein): pLDDT 81.65, 59% of residues very-high.

**13 experimental structure(s)** (PDB): [4DPG](https://www.rcsb.org/structure/4DPG), [4YCU](https://www.rcsb.org/structure/4YCU), [4YCW](https://www.rcsb.org/structure/4YCW), [5A1N](https://www.rcsb.org/structure/5A1N), [5A34](https://www.rcsb.org/structure/5A34), [5A5H](https://www.rcsb.org/structure/5A5H) — incl. mutant structure 4YCW.

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

*Describes the biological roles of AIMP2 (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:** AIMP2's established molecular role includes protein-macromolecule adaptor activity. p.Ser219fs falls in the interaction with tp53 region.


### Pathways affected {#pathways}

AIMP2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cytosolic tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379716) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Selenoamino acid metabolism](https://reactome.org/content/detail/R-HSA-2408522) | electronic |

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

**Molecular function:** protein-macromolecule adaptor activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-12-17.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-21 |
| Breakthrough Genomics, Breakthrough Genomics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-17 |

## Associated conditions {#conditions}

[leukodystrophy, hypomyelinating, 17](https://sugi.bio/atlas/disease/leukodystrophy-hypomyelinating-17/).

**Reported phenotype names (ClinVar):** Leukodystrophy, hypomyelinating, 17.

## Similar variants {#similar}

Related AIMP2 variant pages (same residue, condition, or type): [AIMP2 p.Met24fs](/variant/aimp2-p-met24fs), [AIMP2 p.Tyr35Ter](/variant/aimp2-p-tyr35ter), [AIMP2 p.Thr154=](/variant/aimp2-p-thr154), [AIMP2 p.Val6Leu](/variant/aimp2-p-val6leu), [AIMP2 p.Tyr25Cys](/variant/aimp2-p-tyr25cys), [AIMP2 p.Gln45=](/variant/aimp2-p-gln45), [AIMP2 p.Met24Arg](/variant/aimp2-p-met24arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3062023). 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.*