Is ACACA p.Arg2198Trp (c.6592C>T) pathogenic?

ACACA p.Arg2198Trp (c.6592C>T) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-29). AlphaMissense: likely benign (0.1864); Ultra-rare (popmax 0.0312%, eas); Associated with acetyl-coa carboxylase deficiency.

What condition is associated with ACACA p.Arg2198Trp (c.6592C>T)?

ACACA p.Arg2198Trp (c.6592C>T) is associated with acetyl-coa carboxylase deficiency (ClinVar).

How common is ACACA p.Arg2198Trp (c.6592C>T) in the general population?

ACACA p.Arg2198Trp (c.6592C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about ACACA p.Arg2198Trp (c.6592C>T)?

AlphaMissense predicts likely benign (score 0.1864) — an in-silico prediction, not a clinical call.

ACACA p.Arg2198Trp

c.6592C>T · rs765969361 · VCV2443958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acetyl-coa carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.1864	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -14.20	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.4, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R2161W vs ClinVar R2198W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,890 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00198% 32/1,613,986 alleles · ultra-rare exomes 25/1,461,890 · genomes 7/152,096 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,206
Finnishnot grpmax-eligible	0.00312%	32,016
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00134%	74,870
European (non-Finnish)	0.00102%	98,335

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.Arg2198Trp
Coding: c.6592C>T
MANE Select: NM_198834
dbSNP: rs765969361
Type: single nucleotide variant
Location: chr17:37097958 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2161 UniProt numbering: 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.Arg2198Gln 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-arg2198trp (accessed [today's date]).

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