Is A2M p.Arg586Gln (c.1757G>A) pathogenic?

A2M p.Arg586Gln (c.1757G>A) is classified Likely benign in A2M (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-13). AlphaMissense: likely benign (0.076); Rare (popmax 0.227%, eas); Associated with A2M-related disorder.

What condition is associated with A2M p.Arg586Gln (c.1757G>A)?

A2M p.Arg586Gln (c.1757G>A) is associated with A2M-related disorder (ClinVar).

How common is A2M p.Arg586Gln (c.1757G>A) in the general population?

A2M p.Arg586Gln (c.1757G>A) is rare (popmax 0.227%, eas) (gnomAD).

What do computational predictors say about A2M p.Arg586Gln (c.1757G>A)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

A2M p.Arg586Gln

c.1757G>A · rs190555000 · VCV3034349

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.227%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

A2M-related disorder

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.37	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 -15	GERP -0.96
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	0.031	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 0.227% East Asian · 102/44,852 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.00676% 109/1,612,370 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.227%	440
South Asian	0.00222%	45,117
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)	0.000339%	294,884

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: A2M
Protein: p.Arg586Gln
Coding: c.1757G>A
MANE Select: NM_000014
dbSNP: rs190555000
Type: single nucleotide variant
Location: chr12:9098701 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB

Full A2M gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

A2M-related disorder

Similar variants

A2M p.Arg586Gly Uncertain significance ★ ⚠ same residue
A2M p.Arg586= Likely benign ★ same residue
A2M p.Ala981Ser Uncertain significance ★ ⚠ same condition
A2M c.1495-10T>C Likely benign same condition
A2M c.2597-4T>A Benign same condition
A2M p.Ala844Val Benign same condition
A2M p.Arg704His Benign same condition
A2M p.Asn938Asp Likely benign ⚠ 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/a2m-p-arg586gln (accessed [today's date]).

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