Is ACACA p.Arg2198Gln (c.6593G>A) pathogenic?

ACACA p.Arg2198Gln (c.6593G>A) is classified Uncertain significance in ACACA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0879); Ultra-rare (popmax 0.0142%, nfe); Associated with acetyl-coa carboxylase deficiency.

What condition is associated with ACACA p.Arg2198Gln (c.6593G>A)?

ACACA p.Arg2198Gln (c.6593G>A) is associated with acetyl-coa carboxylase deficiency (ClinVar).

How common is ACACA p.Arg2198Gln (c.6593G>A) in the general population?

ACACA p.Arg2198Gln (c.6593G>A) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Arg2198Gln (c.6593G>A)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

ACACA p.Arg2198Gln

c.6593G>A · rs149967550 · VCV1900468

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

acetyl-coa carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -9.84	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 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	24.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R2161Q vs ClinVar R2198Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0142% European (non-Finnish) · 168/1,180,044 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0128% 206/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
European (non-Finnish)grpmax	0.0142%	7,024
South Asian	0.00988%	10,121
Remaining individualsnot grpmax-eligible	0.0064%	15,623
Finnishnot grpmax-eligible	0.00625%	16,011
East Asian	0.00223%	44,892

Ashkenazi Jewish 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: ACACA
Protein: p.Arg2198Gln
Coding: c.6593G>A
MANE Select: NM_198834
dbSNP: rs149967550
Type: single nucleotide variant
Location: chr17:37097957 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2198: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

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

Disease context

acetyl-coa carboxylase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACACA p.Arg2198Trp Uncertain significance ★ ⚠ same residue
ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same condition
ACACA p.Gln641= Benign ★★ same condition
ACACA p.Ala1548Thr Uncertain significance ★ ⚠ same condition
ACACA p.Ala1657Thr Pathogenic ⚠ same condition
ACACA p.Pro2214His Pathogenic/Likely pathogenic same condition
ACACA c.3474+2TA[14] Uncertain significance ★ same condition
ACACA p.Arg1206His 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/acaca-p-arg2198gln (accessed [today's date]).

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