Is ACAD9 p.Ser268Phe (c.803C>T) pathogenic?

ACAD9 p.Ser268Phe (c.803C>T) is classified Likely pathogenic in ACAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9703); Ultra-rare (popmax 0.0165%, mid); Associated with acyl-CoA dehydrogenase 9 deficiency.

What condition is associated with ACAD9 p.Ser268Phe (c.803C>T)?

ACAD9 p.Ser268Phe (c.803C>T) is associated with acyl-CoA dehydrogenase 9 deficiency (ClinVar).

How common is ACAD9 p.Ser268Phe (c.803C>T) in the general population?

ACAD9 p.Ser268Phe (c.803C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Acyl-CoA dehydrogenase 9 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACAD9 p.Ser268Phe (c.803C>T)?

AlphaMissense predicts likely pathogenic (score 0.9703) — an in-silico prediction, not a clinical call.

ACAD9 p.Ser268Phe

c.803C>T · rs752571732 · VCV1709869

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9703 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acyl-CoA dehydrogenase 9 deficiency

Computational evidence

Protein change
AlphaMissense	0.9703	likely pathogenic ✓ concordant with ClinVar · top 4% in ACAD9
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -15.49	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 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	27.4	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.000508%	196,661

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.Ser268Phe
Coding: c.803C>T
MANE Select: NM_014049
dbSNP: rs752571732
Type: single nucleotide variant
Location: chr3:128899456 (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

Disease context

acyl-CoA dehydrogenase 9 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Acyl-CoA dehydrogenase 9 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ACAD9 c.1150-2A>G Likely pathogenic ★★ same condition
ACAD9 c.1278+1G>T Likely pathogenic ★★ same condition
ACAD9 c.1279-2A>C Likely pathogenic ★★ same condition
ACAD9 c.1358+2T>G Likely pathogenic ★★ same condition
ACAD9 c.1359-1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.1563+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.1A>G Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.453+1G>A Likely pathogenic ★★ same condition

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-ser268phe (accessed [today's date]).

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