Is ACACA p.Arg569Cys (c.1705C>T) pathogenic?

ACACA p.Arg569Cys (c.1705C>T) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.9246); Very rare (popmax 0.004%, afr).

How common is ACACA p.Arg569Cys (c.1705C>T) in the general population?

ACACA p.Arg569Cys (c.1705C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ACACA p.Arg569Cys (c.1705C>T)?

AlphaMissense predicts likely pathogenic (score 0.9246) — an in-silico prediction, not a clinical call.

ACACA p.Arg569Cys

c.1705C>T · VCV4692182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9246	likely pathogenic
REVEL	0.585	indeterminate
SaProt	LLR -13.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 5,358 bp · p 9.3e-19 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R532C vs ClinVar R569C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000991% 16/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
European (non-Finnish)	0.0011%	90,770

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.Arg569Cys
Coding: c.1705C>T
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37257824 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 569: the biotin carboxylation domain; an α-helix

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

Similar variants

ACACA p.Arg569His Uncertain significance ★ ⚠ 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-arg569cys (accessed [today's date]).

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