Is A2M p.Arg704His (c.2111G>A) pathogenic?

A2M p.Arg704His (c.2111G>A) is classified Benign in A2M (ClinVar, No assertion criteria, 1 submitter; last evaluated 1992-04-30). AlphaMissense: likely benign (0.081); Very rare (popmax 0.00253%, sas); Associated with ALPHA-2-MACROGLOBULIN POLYMORPHISM.

What condition is associated with A2M p.Arg704His (c.2111G>A)?

A2M p.Arg704His (c.2111G>A) is associated with ALPHA-2-MACROGLOBULIN POLYMORPHISM (ClinVar).

How common is A2M p.Arg704His (c.2111G>A) in the general population?

A2M p.Arg704His (c.2111G>A) is very rare (popmax 0.00253%, sas) (gnomAD).

What do computational predictors say about A2M p.Arg704His (c.2111G>A)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

A2M p.Arg704His

c.2111G>A · rs1800434 · VCV18174

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALPHA-2-MACROGLOBULIN POLYMORPHISM

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.35	gain · loss 0.25 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.057	GERP -4.1, phastCons 0.001
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	9.764	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 0.00253% South Asian · 2/79,118 alleles

Filtering AF 0.00042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000157%

Overall 0.000512% 8/1,562,640 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00253%	39,559
European (non-Finnish)	0.00052%	192,219

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.Arg704His
Coding: c.2111G>A
MANE Select: NM_000014
dbSNP: rs1800434
Type: single nucleotide variant
Location: chr12:9094987 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB
Residue 704: the 'bait region' region; a disulfide bond; the 'inhibitory' region; a UniProt-annotated variant site (in)

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

Disease context

ALPHA-2-MACROGLOBULIN POLYMORPHISM

Similar variants

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.Arg586Gln Likely benign same condition
A2M p.Asn938Asp Likely benign ⚠ same condition
A2M p.Cys972Tyr Benign same condition
A2M p.Glu1165Gly 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-arg704his (accessed [today's date]).

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