Is A2M p.Ser357Pro (c.1069T>C) pathogenic?

A2M p.Ser357Pro (c.1069T>C) is classified Likely benign in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0764); Very rare (popmax 8.48e-05%, nfe).

How common is A2M p.Ser357Pro (c.1069T>C) in the general population?

A2M p.Ser357Pro (c.1069T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about A2M p.Ser357Pro (c.1069T>C)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

A2M p.Ser357Pro

c.1069T>C · VCV3417232

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.39	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 0.47	GERP 0.43, phastCons 0.29
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	7.849	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 8.48e-05% European (non-Finnish) · 1/1,178,588 alleles

Overall 6.85e-05% 1/1,460,196 alleles · very rare

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.Ser357Pro
Coding: c.1069T>C
MANE Select: NM_000014
Type: single nucleotide variant
Location: chr12:9106271 (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-ser357pro (accessed [today's date]).

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