Is A2M p.Tyr432= (c.1296C>T) pathogenic?

A2M p.Tyr432= (c.1296C>T) is classified Benign in A2M (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-04). Common (popmax 7.98%, sas) — too common for a highly-penetrant pathogenic allele; Associated with A2M-related disorder.

What condition is associated with A2M p.Tyr432= (c.1296C>T)?

A2M p.Tyr432= (c.1296C>T) is associated with A2M-related disorder (ClinVar).

A2M p.Tyr432=

Q: How common is A2M p.Tyr432= (c.1296C>T) in the general population?

A2M p.Tyr432= (c.1296C>T) is common (popmax 7.98%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1296C>T · rs2228222 · VCV3057071

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 7.98%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

A2M-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.6	GERP -5.8
Overall
CADD	0.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.98% South Asian · 7,267/91,020 alleles

Filtering AF 7.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.77%

Overall 5.33% 85,980/1,613,432 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.23%	11
South Asiangrpmax	7.98%	13
Middle Eastern	7.25%	14
European (non-Finnish)	5.71%	18
Remaining individualsnot grpmax-eligible	5.7%	18
Finnishnot grpmax-eligible	3.48%	29
Admixed American	2.79%	36
African / African-American	0.922%	108
East Asian	0.0267%	3,740

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr432=
Coding: c.1296C>T
MANE Select: NM_000014
dbSNP: rs2228222
Type: single nucleotide variant
Location: chr12:9101645 (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.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.Arg704His Benign same condition
A2M p.Asn938Asp Likely benign ⚠ same condition
A2M p.Cys972Tyr 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-tyr432 (accessed [today's date]).

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