Is ACLY p.Ala461Val (c.1382C>T) pathogenic?

ACLY p.Ala461Val (c.1382C>T) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0783); Ultra-rare (popmax 0.0201%, eas).

How common is ACLY p.Ala461Val (c.1382C>T) in the general population?

ACLY p.Ala461Val (c.1382C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about ACLY p.Ala461Val (c.1382C>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

ACLY p.Ala461Val

c.1382C>T · VCV4215962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 30 kb · p 6.3e-16 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0201% East Asian · 9/44,852 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00062% 10/1,613,566 alleles · ultra-rare exomes 10/1,461,284 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,984
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Ala461Val
Coding: c.1382C>T
MANE Select: NM_001096
Type: single nucleotide variant
Location: chr17:41897796 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB
Residue 461: the 'disordered' region

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.Ala467Thr 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-ala461val (accessed [today's date]).

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