Is A2M p.Arg370Cys (c.1108C>T) pathogenic?

A2M p.Arg370Cys (c.1108C>T) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely benign (0.1159); Ultra-rare (popmax 0.0277%, sas).

How common is A2M p.Arg370Cys (c.1108C>T) in the general population?

A2M p.Arg370Cys (c.1108C>T) is ultra-rare (popmax 0.0277%, sas) (gnomAD).

What do computational predictors say about A2M p.Arg370Cys (c.1108C>T)?

AlphaMissense predicts likely benign (score 0.1159) — an in-silico prediction, not a clinical call.

A2M p.Arg370Cys

c.1108C>T · VCV3796640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0277%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1159	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 4.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	25.4	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 0.0277% South Asian · 24/86,550 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.00252% 36/1,429,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0277%	3,606
Admixed American	0.011%	9,113
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,072
East Asian	0.00227%	43,966
Remaining individualsnot grpmax-eligible	0.00163%	61,376
African / African-American	0.00134%	74,466
European (non-Finnish)	0.000172%	581,358

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.Arg370Cys
Coding: c.1108C>T
MANE Select: NM_000014
Type: single nucleotide variant
Location: chr12:9104397 (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

Similar variants

A2M c.3756+4G>A Benign/Likely benign ★★ same type
A2M p.Ala844= Benign ★★ same type
A2M p.Asp277Asn Benign ★★ same type
A2M p.Ile1000Val Benign ★★ same type
A2M p.Pro261Leu Benign ★★ ⚠ same type
A2M p.Tyr1152= Benign/Likely benign ★★ same type
A2M p.Val120= Likely benign ★★ same type
A2M p.Val129= Benign ★★ 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/a2m-p-arg370cys (accessed [today's date]).

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