Is ACACA p.Arg792His (c.2375G>A) pathogenic?

ACACA p.Arg792His (c.2375G>A) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: ambiguous (0.3472); Very rare (popmax 0.00475%, nfe).

How common is ACACA p.Arg792His (c.2375G>A) in the general population?

ACACA p.Arg792His (c.2375G>A) is very rare (popmax 0.00475%, nfe) (gnomAD).

What do computational predictors say about ACACA p.Arg792His (c.2375G>A)?

AlphaMissense predicts ambiguous (score 0.3472) — an in-silico prediction, not a clinical call.

ACACA p.Arg792His

c.2375G>A · VCV3804942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3472	ambiguous
REVEL	0.49	indeterminate
SaProt	LLR -8.54	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 4.1e-22 · regional, not allelic
Overall
CADD	32.0	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 R755H vs ClinVar R792H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00475% European (non-Finnish) · 56/1,179,934 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00378% 61/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,070
Remaining individualsnot grpmax-eligible	0.0032%	31,239
Admixed American	0.00167%	59,986
African / African-American	0.00134%	74,882
South Asian	0.0011%	91,068

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.Arg792His
Coding: c.2375G>A
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37246911 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 792: a β-strand; the biotinyl-binding domain

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

Similar variants

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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
ACACA p.Asp2228Asn 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-arg792his (accessed [today's date]).

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