Is ACLY p.Val715Ala (c.2144T>C) pathogenic?

ACLY p.Val715Ala (c.2144T>C) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: ambiguous (0.5265); Rare (popmax 0.273%, amr).

How common is ACLY p.Val715Ala (c.2144T>C) in the general population?

ACLY p.Val715Ala (c.2144T>C) is rare (popmax 0.273%, amr) (gnomAD).

What do computational predictors say about ACLY p.Val715Ala (c.2144T>C)?

AlphaMissense predicts ambiguous (score 0.5265) — an in-silico prediction, not a clinical call.

ACLY p.Val715Ala

c.2144T>C · rs200021365 · VCV3136896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5265 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.273%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5265	ambiguous
REVEL	0.742	pathogenic-leaning
SaProt	LLR -10.30	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 30 kb · p 6.3e-16 · regional, not allelic
Overall
CADD	27.0	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 0.273% Admixed American · 164/59,972 alleles

Filtering AF 0.239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.226%

Overall 0.0123% 198/1,603,398 alleles · rare exomes 77/1,451,118 · genomes 121/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.273%	366
African / African-American	0.0214%	4,675
Middle Eastern	0.0166%	6,038
Remaining individualsnot grpmax-eligible	0.00483%	20,707
European (non-Finnish)	0.00111%	90,030
South Asian	0.0011%	90,788

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.Val715Ala
Coding: c.2144T>C
MANE Select: NM_001096
dbSNP: rs200021365
Type: single nucleotide variant
Location: chr17:41884203 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB
Residue 715: 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-val715ala (accessed [today's date]).

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