Is AIMP2 p.Phe218Leu (c.654C>G) pathogenic?

AIMP2 p.Phe218Leu (c.654C>G) is classified Uncertain significance in AIMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.9017); Absent from gnomAD v4.1.

How common is AIMP2 p.Phe218Leu (c.654C>G) in the general population?

AIMP2 p.Phe218Leu (c.654C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AIMP2 p.Phe218Leu (c.654C>G)?

AlphaMissense predicts likely pathogenic (score 0.9017) — an in-silico prediction, not a clinical call.

AIMP2 p.Phe218Leu

c.654C>G · rs2536857516 · VCV1946194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9017 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9017	likely pathogenic
REVEL	0.161	moderately benign-leaning
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 14 kb · p 8e-07 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AIMP2
Protein: p.Phe218Leu
Coding: c.654C>G
MANE Select: NM_006303
dbSNP: rs2536857516
Type: single nucleotide variant
Location: chr7:6023382 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65 · 13 PDB
Residue 218: 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

Similar variants

PMS2 c.-2146C>A Benign ★★★ same type
PMS2 c.-2559T>A Benign ★★★ same type
PMS2 c.-323G>T Benign ★★★ same type
AIMP2 p.Tyr35Ter Likely pathogenic ★★ same type
AIMP2 p.Ala240Val Uncertain significance ★★ ⚠ same type
AIMP2 p.Arg215Cys Uncertain significance ★★ ⚠ same type
AIMP2 p.Arg215His Uncertain significance ★★ ⚠ same type
AIMP2 p.Arg33Lys Uncertain significance ★★ ⚠ same type

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-phe218leu (accessed [today's date]).

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