Is ACACA p.Pro699fs (c.2094del) pathogenic?

ACACA p.Pro699fs (c.2094del) is classified Uncertain significance in ACACA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-21). Very rare (popmax 0.00034%, nfe); Associated with ACACA-related disorder.

What condition is associated with ACACA p.Pro699fs (c.2094del)?

ACACA p.Pro699fs (c.2094del) is associated with ACACA-related disorder (ClinVar).

How common is ACACA p.Pro699fs (c.2094del) in the general population?

ACACA p.Pro699fs (c.2094del) is very rare (popmax 0.00034%, nfe) (gnomAD).

ACACA p.Pro699fs

c.2094del · VCV3358815

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Conditions

ACACA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 17 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.2	GERP 0.13, phastCons 1
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,177,006 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,609,840 alleles · very rare

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.Pro699fs
Coding: c.2094del
MANE Select: NM_198834
Type: Deletion
Location: chr17:37248662 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB

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

Disease context

ACACA-related disorder

Similar variants

ACACA c.4777-8del Likely benign same condition
ACACA c.5569-10C>G Likely benign same condition
ACACA p.Asn990= Likely benign same condition
ACACA p.Leu1734= Likely benign same condition
ACACA p.Ser789= Likely benign same condition
ACACA p.Val2008= Likely benign same condition
ACACA p.Arg148fs Uncertain significance ★ same type
ACACA p.Gly1985fs 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-pro699fs (accessed [today's date]).

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