Is ACACA p.Arg2232Trp (c.6694C>T) pathogenic?

ACACA p.Arg2232Trp (c.6694C>T) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: ambiguous (0.395); Very rare (popmax 8.47e-05%, nfe).

How common is ACACA p.Arg2232Trp (c.6694C>T) in the general population?

ACACA p.Arg2232Trp (c.6694C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Arg2232Trp (c.6694C>T)?

AlphaMissense predicts ambiguous (score 0.395) — an in-silico prediction, not a clinical call.

ACACA p.Arg2232Trp

c.6694C>T · rs1273138717 · VCV2333287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.395	ambiguous
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -16.30	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	33.0	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 R2195W vs ClinVar R2232W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 0.000657% 1/152,108 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: ACACA
Protein: p.Arg2232Trp
Coding: c.6694C>T
MANE Select: NM_198834
dbSNP: rs1273138717
Type: single nucleotide variant
Location: chr17:37097856 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2232: 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

Similar variants

ACACA p.Arg2232= Likely benign ★ same residue
ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same type
ACACA p.Arg1206His Uncertain significance ★★ ⚠ same type
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same type
ACACA p.Arg745Trp Uncertain significance ★★ ⚠ same type
ACACA p.Asn1903Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn950Ser 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-arg2232trp (accessed [today's date]).

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