Is A2M p.Pro591Ser (c.1771C>T) pathogenic?

A2M p.Pro591Ser (c.1771C>T) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely benign (0.1237); Very rare (popmax 0.00335%, amr).

How common is A2M p.Pro591Ser (c.1771C>T) in the general population?

A2M p.Pro591Ser (c.1771C>T) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about A2M p.Pro591Ser (c.1771C>T)?

AlphaMissense predicts likely benign (score 0.1237) — an in-silico prediction, not a clinical call.

A2M p.Pro591Ser

c.1771C>T · VCV3264313

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1237	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -9.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 4.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00335% Admixed American · 2/59,788 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000372% 6/1,612,004 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,894
South Asian	0.00222%	45,068
European (non-Finnish)	0.00017%	589,717

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.Pro591Ser
Coding: c.1771C>T
MANE Select: NM_000014
Type: single nucleotide variant
Location: chr12:9098687 (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-pro591ser (accessed [today's date]).

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