Is ACACA p.Asp1044Glu (c.3132C>G) pathogenic?

ACACA p.Asp1044Glu (c.3132C>G) is classified Conflicting classifications of pathogenicity in ACACA (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.5869); Rare (popmax 0.314%, mid).

How common is ACACA p.Asp1044Glu (c.3132C>G) in the general population?

ACACA p.Asp1044Glu (c.3132C>G) is rare (popmax 0.314%, mid) (gnomAD).

What do computational predictors say about ACACA p.Asp1044Glu (c.3132C>G)?

AlphaMissense predicts likely pathogenic (score 0.5869) — an in-silico prediction, not a clinical call.

ACACA p.Asp1044Glu

c.3132C>G · rs140628687 · VCV1049285

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5869 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.314%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5869	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -3.00	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 4.1e-22 · regional, not allelic
Overall
CADD	20.7	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 D1007E vs ClinVar D1044E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.314% Middle Eastern · 19/6,060 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0596% 962/1,613,292 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.66%	60
Middle Easterngrpmax	0.314%	319
Remaining individualsnot grpmax-eligible	0.158%	631
Admixed American	0.04%	2,500
European (non-Finnish)	0.0268%	3,734
African / African-American	0.016%	6,245

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp1044Glu
Coding: c.3132C>G
MANE Select: NM_198834
dbSNP: rs140628687
Type: single nucleotide variant
Location: chr17:37235089 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 1044: an α-helix

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

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ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
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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-asp1044glu (accessed [today's date]).

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