Is ACACA p.Leu1674Val (c.5020C>G) pathogenic?

ACACA p.Leu1674Val (c.5020C>G) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). AlphaMissense: ambiguous (0.4699); Ultra-rare (popmax 0.025%, amr).

How common is ACACA p.Leu1674Val (c.5020C>G) in the general population?

ACACA p.Leu1674Val (c.5020C>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ACACA p.Leu1674Val (c.5020C>G)?

AlphaMissense predicts ambiguous (score 0.4699) — an in-silico prediction, not a clinical call.

ACACA p.Leu1674Val

c.5020C>G · VCV4690877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4699 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4699	ambiguous
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -11.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	23.3	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 L1637V vs ClinVar L1674V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/59,994 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.000929% 15/1,614,032 alleles · ultra-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.Leu1674Val
Coding: c.5020C>G
MANE Select: NM_198834
Type: single nucleotide variant
Location: chr17:37179319 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 1674: the coa carboxyltransferase n-terminal domain; the 'carboxyltransferase' region

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

Similar variants

ACACA p.Leu1674Met Uncertain significance ★ ⚠ same residue
ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same type
ACACA p.Arg1206His Uncertain significance ★★ ⚠ same type
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same type
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

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-leu1674val (accessed [today's date]).

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