Is ACACA p.Arg569His (c.1706G>A) pathogenic?

ACACA p.Arg569His (c.1706G>A) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.8243); Very rare (popmax 0.00339%, nfe).

How common is ACACA p.Arg569His (c.1706G>A) in the general population?

ACACA p.Arg569His (c.1706G>A) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Arg569His (c.1706G>A)?

AlphaMissense predicts likely pathogenic (score 0.8243) — an in-silico prediction, not a clinical call.

ACACA p.Arg569His

c.1706G>A · VCV4196691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8243	likely pathogenic
REVEL	0.48	indeterminate
SaProt	LLR -12.58	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 7.6	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	32.0	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 R532H vs ClinVar R569H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,180,026 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00285% 46/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,501
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
African / African-American	0.00267%	37,454
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,090

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.Arg569His
Coding: c.1706G>A
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37257823 (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.Arg569Cys 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-arg569his (accessed [today's date]).

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