Is A2M p.Asp274= (c.822C>T) pathogenic?

A2M p.Asp274= (c.822C>T) is classified Likely benign in A2M (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-31). Rare (popmax 0.148%, nfe).

How common is A2M p.Asp274= (c.822C>T) in the general population?

A2M p.Asp274= (c.822C>T) is rare (popmax 0.148%, nfe) (gnomAD).

A2M p.Asp274=

c.822C>T · rs202126909 · VCV714548

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.148%, nfe)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.061	GERP -7.5
Overall
CADD	3.374	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% European (non-Finnish) · 1,742/1,179,872 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.139%

Overall 0.116% 1,880/1,613,968 alleles · rare exomes 1,760/1,461,658 · genomes 120/152,310 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.148%	677
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0976%	1,024
Admixed American	0.055%	1,819
African / African-American	0.0333%	3,002
South Asian	0.0143%	7,006

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.Asp274=
Coding: c.822C>T
MANE Select: NM_000014
dbSNP: rs202126909
Type: single nucleotide variant
Location: chr12:9107581 (GRCh38)

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

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-asp274 (accessed [today's date]).

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