Is ACLY p.Pro693Leu (c.2078C>T) pathogenic?

ACLY p.Pro693Leu (c.2078C>T) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely pathogenic (0.9426); Rare (popmax 0.102%, sas).

How common is ACLY p.Pro693Leu (c.2078C>T) in the general population?

ACLY p.Pro693Leu (c.2078C>T) is rare (popmax 0.102%, sas) (gnomAD).

What do computational predictors say about ACLY p.Pro693Leu (c.2078C>T)?

AlphaMissense predicts likely pathogenic (score 0.9426) — an in-silico prediction, not a clinical call.

ACLY p.Pro693Leu

c.2078C>T · rs532952188 · VCV3136887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9426 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9426	likely pathogenic
REVEL	0.764	pathogenic-leaning
SaProt	LLR -15.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 30 kb · p 6.3e-16 · regional, not allelic
Overall
CADD	27.3	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 0.102% South Asian · 93/90,944 alleles

Filtering AF 0.0855% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0792%

Overall 0.0101% 163/1,607,996 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.102%	978
East Asian	0.0803%	1,246
African / African-American	0.00935%	10,694
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.00321%	31,145
European (non-Finnish)	0.00179%	55,930

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.Pro693Leu
Coding: c.2078C>T
MANE Select: NM_001096
dbSNP: rs532952188
Type: single nucleotide variant
Location: chr17:41884269 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB

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-pro693leu (accessed [today's date]).

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