Is ACACA p.Gln1084His (c.3252G>T) pathogenic?

ACACA p.Gln1084His (c.3252G>T) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.2731); Ultra-rare (popmax 0.029%, eas).

How common is ACACA p.Gln1084His (c.3252G>T) in the general population?

ACACA p.Gln1084His (c.3252G>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about ACACA p.Gln1084His (c.3252G>T)?

AlphaMissense predicts likely benign (score 0.2731) — an in-silico prediction, not a clinical call.

ACACA p.Gln1084His

c.3252G>T · rs372356309 · VCV2205319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2731	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP -0.96, phastCons 0.87
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 4.1e-22 · regional, not allelic
Overall
CADD	18.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 Q1047H vs ClinVar Q1084H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,892 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000868% 14/1,612,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,453
African / African-American	0.00134%	74,832

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.Gln1084His
Coding: c.3252G>T
MANE Select: NM_198834
dbSNP: rs372356309
Type: single nucleotide variant
Location: chr17:37226447 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 1084: 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-gln1084his (accessed [today's date]).

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