Is A2M p.Thr797Ile (c.2390C>T) pathogenic?

A2M p.Thr797Ile (c.2390C>T) is classified Uncertain significance in A2M (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). AlphaMissense: likely benign (0.2349); Very rare (popmax 0.00267%, afr).

How common is A2M p.Thr797Ile (c.2390C>T) in the general population?

A2M p.Thr797Ile (c.2390C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about A2M p.Thr797Ile (c.2390C>T)?

AlphaMissense predicts likely benign (score 0.2349) — an in-silico prediction, not a clinical call.

A2M p.Thr797Ile

c.2390C>T · rs779160830 · VCV2288432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2349 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2349	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -9.73	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 5.1	GERP 4.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	23.1	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 0.00267% African / African-American · 2/74,908 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,072 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,454
Admixed American	0.00167%	60,012

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.Thr797Ile
Coding: c.2390C>T
MANE Select: NM_000014
dbSNP: rs779160830
Type: single nucleotide variant
Location: chr12:9091280 (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-thr797ile (accessed [today's date]).

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