Is A2M p.Ile1000Val (c.2998A>G) pathogenic?

A2M p.Ile1000Val (c.2998A>G) is classified Benign in A2M (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-29). AlphaMissense: likely benign (0.0696); Common (popmax 37.7%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about A2M p.Ile1000Val (c.2998A>G)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

A2M p.Ile1000Val

Q: How common is A2M p.Ile1000Val (c.2998A>G) in the general population?

A2M p.Ile1000Val (c.2998A>G) is common (popmax 37.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2998A>G · rs669 · VCV18171

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 37.7%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.27	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 -0.93	GERP -1.5
Regional constraint	o/e 0.84	unconstrained · MANE · 48 kb · p 4.5e-12 · regional, not allelic
Overall
CADD	11.73	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 37.7% Admixed American · 22,580/59,872 alleles

Filtering AF 37.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.1%

Overall 32.8% 529,148/1,612,050 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	40.8%	2
Admixed Americangrpmax	37.7%	3
European (non-Finnish)	34.7%	3
Remaining individualsnot grpmax-eligible	30.7%	3
African / African-American	30%	3
Amishnot grpmax-eligible	27.5%	4
Middle Eastern	24.3%	4
Ashkenazi Jewishnot grpmax-eligible	23.6%	4
South Asian	20.2%	5
East Asian	7.61%	13

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile1000Val
Coding: c.2998A>G
MANE Select: NM_000014
dbSNP: rs669
Type: single nucleotide variant
Location: chr12:9079672 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.61 · 13 PDB
Residue 1000: a disulfide bond; a UniProt-annotated variant site (in)

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.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
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-ile1000val (accessed [today's date]).

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