Is ACLY p.Leu833Phe (c.2499G>C) pathogenic?

ACLY p.Leu833Phe (c.2499G>C) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.9611); Very rare (popmax 0.000171%, nfe).

How common is ACLY p.Leu833Phe (c.2499G>C) in the general population?

ACLY p.Leu833Phe (c.2499G>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about ACLY p.Leu833Phe (c.2499G>C)?

AlphaMissense predicts likely pathogenic (score 0.9611) — an in-silico prediction, not a clinical call.

ACLY p.Leu833Phe

c.2499G>C · VCV3824070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9611	likely pathogenic
REVEL	0.316	indeterminate
SaProt	LLR -13.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -1.2, phastCons 0.99
Regional constraint	o/e 0.55	unconstrained · MANE · 10 kb · p 3e-18 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,172,556 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,602,826 alleles · very rare exomes 2/1,450,508 · genomes 0/152,318 · joint denominator

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: ACLY
Protein: p.Leu833Phe
Coding: c.2499G>C
MANE Select: NM_001096
Type: single nucleotide variant
Location: chr17:41873954 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB
Residue 833: a β-strand

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

Similar variants

ACLY p.Gln314= Benign ★★ same type
ACLY p.Val286= Benign ★★ same type
ACLY p.Ala1032Thr Uncertain significance ★ ⚠ same type
ACLY p.Ala173Ser Uncertain significance ★ ⚠ same type
ACLY p.Ala173Thr Uncertain significance ★ ⚠ same type
ACLY p.Ala24Thr Uncertain significance ★ ⚠ same type
ACLY p.Ala432Thr Uncertain significance ★ ⚠ same type
ACLY p.Ala461Val 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/acly-p-leu833phe (accessed [today's date]).

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