Is ACACA p.Lys2164Arg (c.6491A>G) pathogenic?

ACACA p.Lys2164Arg (c.6491A>G) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.1156); Ultra-rare (popmax 0.0103%, nfe).

How common is ACACA p.Lys2164Arg (c.6491A>G) in the general population?

ACACA p.Lys2164Arg (c.6491A>G) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Lys2164Arg (c.6491A>G)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

ACACA p.Lys2164Arg

c.6491A>G · VCV3260323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.623	indeterminate
SaProt	LLR -12.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.3, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	21.3	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 K2127R vs ClinVar K2164R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 122/1,180,036 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00805% 130/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,672
African / African-American	0.00801%	12,489
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Lys2164Arg
Coding: c.6491A>G
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37111605 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2164: 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

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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
ACACA p.Asp2228Asn 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-lys2164arg (accessed [today's date]).

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