Is A2M p.Pro261Leu (c.782C>T) pathogenic?

A2M p.Pro261Leu (c.782C>T) is classified Benign in A2M (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-16). AlphaMissense: likely benign (0.1153); Low-frequency (popmax 4.16%, amr).

How common is A2M p.Pro261Leu (c.782C>T) in the general population?

A2M p.Pro261Leu (c.782C>T) is low-frequency (popmax 4.16%, amr) (gnomAD).

What do computational predictors say about A2M p.Pro261Leu (c.782C>T)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

A2M p.Pro261Leu

c.782C>T · rs182493380 · VCV770606

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.16%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.77	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 5.1	GERP 3.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	19.77	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 4.16% Admixed American · 2,499/60,016 alleles

Filtering AF 4.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.97%

Overall 0.162% 2,608/1,613,946 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.16%	24
Remaining individualsnot grpmax-eligible	0.102%	976
African / African-American	0.036%	2,779
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.00144%	69,405

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.Pro261Leu
Coding: c.782C>T
MANE Select: NM_000014
dbSNP: rs182493380
Type: single nucleotide variant
Location: chr12:9107621 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB
Residue 261: a disulfide bond

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.Tyr1152= Benign/Likely benign ★★ same type
A2M p.Val120= Likely benign ★★ same type
A2M p.Val129= Benign ★★ same type
A2M p.Val437= 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-pro261leu (accessed [today's date]).

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