Is A2M p.Val940Glu (c.2819T>A) pathogenic?

A2M p.Val940Glu (c.2819T>A) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.6011); Absent from gnomAD v4.1.

How common is A2M p.Val940Glu (c.2819T>A) in the general population?

A2M p.Val940Glu (c.2819T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about A2M p.Val940Glu (c.2819T>A)?

AlphaMissense predicts likely pathogenic (score 0.6011) — an in-silico prediction, not a clinical call.

A2M p.Val940Glu

c.2819T>A · VCV4227338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6011 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,590,988)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6011	likely pathogenic
REVEL	0.371	indeterminate
SaProt	LLR -10.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 5.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,590,988). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: A2M
Protein: p.Val940Glu
Coding: c.2819T>A
MANE Select: NM_000014
Type: single nucleotide variant
Location: chr12:9080129 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB
Residue 940: 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.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-val940glu (accessed [today's date]).

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