Is ACLY p.Phe950Ser (c.2849T>C) pathogenic?

ACLY p.Phe950Ser (c.2849T>C) is classified Uncertain significance in ACLY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4126); Very rare (popmax 8.47e-05%, nfe).

How common is ACLY p.Phe950Ser (c.2849T>C) in the general population?

ACLY p.Phe950Ser (c.2849T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACLY p.Phe950Ser (c.2849T>C)?

AlphaMissense predicts ambiguous (score 0.4126) — an in-silico prediction, not a clinical call.

ACLY p.Phe950Ser

c.2849T>C · VCV4216129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4126	ambiguous
REVEL	0.639	indeterminate
SaProt	LLR -11.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 10 kb · p 3e-18 · regional, not allelic
Overall
CADD	25.6	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.84e-05% 1/1,461,832 alleles · very rare

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.Phe950Ser
Coding: c.2849T>C
MANE Select: NM_001096
Type: single nucleotide variant
Location: chr17:41871777 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.61 · 36 PDB
Residue 950: an α-helix

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-phe950ser (accessed [today's date]).

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