Is ACAA2 p.Met217Val (c.649A>G) pathogenic?

ACAA2 p.Met217Val (c.649A>G) is classified Benign in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.0829); Common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ACAA2 p.Met217Val (c.649A>G)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

ACAA2 p.Met217Val

Q: How common is ACAA2 p.Met217Val (c.649A>G) in the general population?

ACAA2 p.Met217Val (c.649A>G) is common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.649A>G · VCV4684286

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -3.43	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 -1.4	GERP -1.8
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	0.968	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 15.4% East Asian · 6,903/44,872 alleles

Filtering AF 15.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 15%

Overall 2.45% 39,480/1,613,844 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	15.4%	7
South Asian	6.36%	16
Ashkenazi Jewishnot grpmax-eligible	5.31%	19
Admixed American	4.04%	25
Remaining individualsnot grpmax-eligible	3.12%	32
Middle Eastern	2.63%	38
Finnishnot grpmax-eligible	2.15%	46
European (non-Finnish)	1.61%	62
Amishnot grpmax-eligible	1.43%	70
African / African-American	0.368%	272

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: ACAA2
Protein: p.Met217Val
Coding: c.649A>G
MANE Select: NM_006111
Type: single nucleotide variant
Location: chr18:49792256 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.49 · 2 PDB
Residue 217: a UniProt-annotated variant site (in); a β-strand

Full ACAA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAA2 p.Met217Thr Uncertain significance ★ ⚠ same residue
ACAA2 p.Tyr198Asn Benign ★★ same type
ACAA2 p.Ala183Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala196Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala250Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala267Gly Uncertain significance ★ ⚠ same type
ACAA2 p.Ala70Ser Uncertain significance ★ ⚠ same type
ACAA2 p.Arg133His Uncertain significance ★ ⚠ 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/acaa2-p-met217val (accessed [today's date]).

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