Is AIM2 p.Arg226Cys (c.676C>T) pathogenic?

AIM2 p.Arg226Cys (c.676C>T) is classified Likely benign in AIM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.005%, amr).

How common is AIM2 p.Arg226Cys (c.676C>T) in the general population?

AIM2 p.Arg226Cys (c.676C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AIM2 p.Arg226Cys (c.676C>T)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

AIM2 p.Arg226Cys

c.676C>T · VCV3279007

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.3	GERP -2.8
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.0086 · regional, not allelic
Overall
CADD	0.197	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 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00149% 24/1,613,986 alleles · very rare exomes 23/1,461,840 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
South Asian	0.00439%	22,773
East Asian	0.00223%	44,900
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,910
European (non-Finnish)	0.00119%	84,288

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: AIM2
Protein: p.Arg226Cys
Coding: c.676C>T
MANE Select: NM_004833
Type: single nucleotide variant
Location: chr1:159066050 (GRCh38)
Gene constraint: LOEUF 1.421 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 6 PDB
Residue 226: the hin-200 domain; a β-strand

Full AIM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AIM2 p.Arg226His Uncertain significance ★ ⚠ same residue
AIM2 p.Arg226Leu Uncertain significance ★ ⚠ same residue
AIM2 c.396+6A>T Benign ★★ same type
AIM2 p.Glu83= Benign ★★ same type
AIM2 p.Pro250= Benign ★★ same type
AIM2 p.Ala112Ser Uncertain significance ★ ⚠ same type
AIM2 p.Ala230Val Uncertain significance ★ ⚠ same type
AIM2 p.Arg115Gly 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/aim2-p-arg226cys (accessed [today's date]).

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