Is AIMP2 p.Arg178His (c.533G>A) pathogenic?

AIMP2 p.Arg178His (c.533G>A) is classified Uncertain significance in AIMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.6278); Very rare (popmax 0.0011%, sas).

How common is AIMP2 p.Arg178His (c.533G>A) in the general population?

AIMP2 p.Arg178His (c.533G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AIMP2 p.Arg178His (c.533G>A)?

AlphaMissense predicts likely pathogenic (score 0.6278) — an in-silico prediction, not a clinical call.

AIMP2 p.Arg178His

c.533G>A · rs766723249 · VCV1930673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6278	likely pathogenic
REVEL	0.298	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 14 kb · p 8e-07 · regional, not allelic
Overall
CADD	26.2	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 0.0011% South Asian · 1/91,060 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,804 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.000932%	107,272

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.Arg178His
Coding: c.533G>A
MANE Select: NM_006303
dbSNP: rs766723249
Type: single nucleotide variant
Location: chr7:6018004 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.65 · 13 PDB
Residue 178: 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

Similar variants

AIMP2 p.Arg178Cys Uncertain significance ★ ⚠ same residue
AIMP2 p.Arg178Leu Uncertain significance ★ ⚠ same residue
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

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-arg178his (accessed [today's date]).

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