Is ACACA p.Ala1657Thr (c.4969G>A) pathogenic?

ACACA p.Ala1657Thr (c.4969G>A) is classified Pathogenic in ACACA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.0913); Ultra-rare (popmax 0.0245%, eas); Associated with acetyl-coa carboxylase deficiency.

What condition is associated with ACACA p.Ala1657Thr (c.4969G>A)?

ACACA p.Ala1657Thr (c.4969G>A) is associated with acetyl-coa carboxylase deficiency (ClinVar).

How common is ACACA p.Ala1657Thr (c.4969G>A) in the general population?

ACACA p.Ala1657Thr (c.4969G>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about ACACA p.Ala1657Thr (c.4969G>A)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

ACACA p.Ala1657Thr

c.4969G>A · rs749657231 · VCV2443957

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

acetyl-coa carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign ⚠ discordant with ClinVar
REVEL	0.453	indeterminate
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	23.7	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 A1620T vs ClinVar A1657T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,884 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00118% 19/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,088
European (non-Finnish)	0.000508%	196,666

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.Ala1657Thr
Coding: c.4969G>A
MANE Select: NM_198834
dbSNP: rs749657231
Type: single nucleotide variant
Location: chr17:37179370 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 1657: a β-strand; the coa carboxyltransferase n-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.Ala2308Val Uncertain significance ★★ ⚠ same condition
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same condition
ACACA p.Gln641= Benign ★★ same condition
ACACA p.Ala1548Thr Uncertain significance ★ ⚠ same condition
ACACA p.Arg2198Trp Uncertain significance ★ ⚠ 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-ala1657thr (accessed [today's date]).

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