Is ACAD9 p.Ser474Thr (c.1420T>A) pathogenic?

ACAD9 p.Ser474Thr (c.1420T>A) is classified Uncertain significance in ACAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-18). AlphaMissense: likely benign (0.0787); Very rare (popmax 0.00167%, amr).

How common is ACAD9 p.Ser474Thr (c.1420T>A) in the general population?

ACAD9 p.Ser474Thr (c.1420T>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ACAD9 p.Ser474Thr (c.1420T>A)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

ACAD9 p.Ser474Thr

c.1420T>A · rs1194653869 · VCV1384237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP 0.42, phastCons 0.002
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	6.108	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 0.00167% Admixed American · 1/60,024 alleles

Overall 6.84e-05% 1/1,461,816 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: ACAD9
Protein: p.Ser474Thr
Coding: c.1420T>A
MANE Select: NM_014049
dbSNP: rs1194653869
Type: single nucleotide variant
Location: chr3:128909034 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 2 PDB

Full ACAD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAD9 p.Ser474Phe Uncertain significance ★ ⚠ same residue
ACAD9 p.Ser474= Likely benign ★ same residue
ACAD9 c.1030-1G>A Pathogenic/Likely pathogenic ★★ same type
ACAD9 c.1150-2A>G Likely pathogenic ★★ same type
ACAD9 c.1278+1G>T Likely pathogenic ★★ same type
ACAD9 c.1279-2A>C Likely pathogenic ★★ same type
ACAD9 c.1358+2T>G Likely pathogenic ★★ same type
ACAD9 c.1359-1G>A Pathogenic/Likely pathogenic ★★ 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/acad9-p-ser474thr (accessed [today's date]).

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