Is ACAA2 p.Met217Thr (c.650T>C) pathogenic?

ACAA2 p.Met217Thr (c.650T>C) is classified Uncertain significance in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-22). AlphaMissense: likely pathogenic (0.5776); Very rare (popmax 0.0011%, sas).

How common is ACAA2 p.Met217Thr (c.650T>C) in the general population?

ACAA2 p.Met217Thr (c.650T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACAA2 p.Met217Thr (c.650T>C)?

AlphaMissense predicts likely pathogenic (score 0.5776) — an in-silico prediction, not a clinical call.

ACAA2 p.Met217Thr

c.650T>C · rs747783652 · VCV2313093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5776	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	21.5	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 0.0011% South Asian · 1/91,064 alleles

Overall 6.84e-05% 1/1,461,738 alleles · very rare

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.Met217Thr
Coding: c.650T>C
MANE Select: NM_006111
dbSNP: rs747783652
Type: single nucleotide variant
Location: chr18:49792255 (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.Met217Val Benign ★ 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-met217thr (accessed [today's date]).

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