Is ACLY p.Val156Met (c.466G>A) pathogenic?

ACLY p.Val156Met (c.466G>A) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: ambiguous (0.3454); Very rare (popmax 0.000424%, nfe).

How common is ACLY p.Val156Met (c.466G>A) in the general population?

ACLY p.Val156Met (c.466G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ACLY p.Val156Met (c.466G>A)?

AlphaMissense predicts ambiguous (score 0.3454) — an in-silico prediction, not a clinical call.

ACLY p.Val156Met

c.466G>A · rs782467741 · VCV2547991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3454 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3454	ambiguous
REVEL	0.48	indeterminate
SaProt	LLR -10.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,853 bp · p 0.24 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,034 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,192 alleles · very rare exomes 7/1,461,890 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)grpmax	0.000424%	236,007

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val156Met
Coding: c.466G>A
MANE Select: NM_001096
dbSNP: rs782467741
Type: single nucleotide variant
Location: chr17:41909580 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB
Residue 156: the atp-grasp domain

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-val156met (accessed [today's date]).

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