Is AIMP2 p.Leu76Phe (c.226C>T) pathogenic?

AIMP2 p.Leu76Phe (c.226C>T) is classified Uncertain significance in AIMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-14). AlphaMissense: ambiguous (0.5466); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AIMP2 p.Leu76Phe (c.226C>T)?

AIMP2 p.Leu76Phe (c.226C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AIMP2 p.Leu76Phe (c.226C>T) in the general population?

AIMP2 p.Leu76Phe (c.226C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AIMP2 p.Leu76Phe (c.226C>T)?

AlphaMissense predicts ambiguous (score 0.5466) — an in-silico prediction, not a clinical call.

AIMP2 p.Leu76Phe

c.226C>T · rs765088234 · VCV986028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5466	ambiguous
REVEL	0.33	indeterminate
SaProt	LLR -9.56	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 14 kb · p 8e-07 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,614,136 alleles · very rare exomes 1/1,461,882 · genomes 0/152,254 · joint denominator

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.Leu76Phe
Coding: c.226C>T
MANE Select: NM_006303
dbSNP: rs765088234
Type: single nucleotide variant
Location: chr7:6015236 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65 · 13 PDB
Residue 76: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AIMP2 p.Ala240Val Uncertain significance ★★ same condition
AIMP2 p.Arg215Cys Uncertain significance ★★ ⚠ same condition
AIMP2 p.Arg215His Uncertain significance ★★ ⚠ same condition
AIMP2 p.Arg33Lys Uncertain significance ★★ ⚠ same condition
AIMP2 p.Arg58Cys Uncertain significance ★★ ⚠ same condition
AIMP2 p.Arg58His Uncertain significance ★★ ⚠ same condition
AIMP2 p.Asn226Ser Uncertain significance ★★ ⚠ same condition
AIMP2 p.Asn29Lys 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-leu76phe (accessed [today's date]).

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