Is AIMP2 p.Ser219fs (c.656_659del) pathogenic?

AIMP2 p.Ser219fs (c.656659del) 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.

What condition is associated with AIMP2 p.Ser219fs (c.656_659del)?

AIMP2 p.Ser219fs (c.656_659del) is associated with leukodystrophy, hypomyelinating, 17 (ClinVar).

How common is AIMP2 p.Ser219fs (c.656_659del) in the general population?

AIMP2 p.Ser219fs (c.656_659del) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

AIMP2 p.Ser219fs

c.656_659del · rs760123492 · VCV3062023

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

leukodystrophy, hypomyelinating, 17

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,942 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00124% 20/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,813
East Asian	0.00445%	22,447
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)	0.000508%	196,672

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AIMP2
Protein: p.Ser219fs
Coding: c.656_659del
MANE Select: NM_006303
dbSNP: rs760123492
Type: Microsatellite
Location: chr7:6023381 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65 · 13 PDB
Residue 219: the 'interaction with tp53' region; an α-helix; a UniProt-annotated variant site (in hld17)

Full AIMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukodystrophy, hypomyelinating, 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AIMP2 p.Met24fs Pathogenic/Likely pathogenic ★★ same condition
AIMP2 p.Tyr35Ter Likely pathogenic ★★ same condition
AIMP2 p.Thr154= Benign/Likely benign ★★ same condition
AIMP2 p.Val6Leu Benign/Likely benign ★★ same condition
AIMP2 p.Tyr25Cys Likely pathogenic ★ ⚠ same condition
AIMP2 p.Gln45= Uncertain significance ★ same condition
AIMP2 p.Met24Arg Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aimp2-p-ser219fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown