Is AIMP2 p.Phe221Leu (c.663T>G) pathogenic?

AIMP2 p.Phe221Leu (c.663T>G) is classified Uncertain significance in AIMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.5742); Very rare (popmax 0.000847%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AIMP2 p.Phe221Leu (c.663T>G)?

AIMP2 p.Phe221Leu (c.663T>G) is associated with Inborn genetic diseases (ClinVar).

How common is AIMP2 p.Phe221Leu (c.663T>G) in the general population?

AIMP2 p.Phe221Leu (c.663T>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about AIMP2 p.Phe221Leu (c.663T>G)?

AlphaMissense predicts likely pathogenic (score 0.5742) — an in-silico prediction, not a clinical call.

AIMP2 p.Phe221Leu

c.663T>G · VCV4573649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5742	likely pathogenic
REVEL	0.112	moderately benign-leaning
SaProt	LLR -3.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.75	phastCons 0.02
Regional constraint	o/e 1.24	unconstrained · MANE · 14 kb · p 8e-07 · regional, not allelic
Overall
CADD	14.2	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 0.000847% European (non-Finnish) · 10/1,180,046 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000743% 12/1,614,088 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.000847%	118,005

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe221Leu
Coding: c.663T>G
MANE Select: NM_006303
Type: single nucleotide variant
Location: chr7:6023391 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65 · 13 PDB
Residue 221: the gst c-terminal domain; the 'interaction with tp53' region; 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-phe221leu (accessed [today's date]).

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