Is ACAD8 p.Ser98Phe (c.293C>T) pathogenic?

ACAD8 p.Ser98Phe (c.293C>T) is classified Uncertain significance in ACAD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-15). AlphaMissense: ambiguous (0.3721); Absent from gnomAD v4.1; Associated with isobutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACAD8 p.Ser98Phe (c.293C>T)?

ACAD8 p.Ser98Phe (c.293C>T) is associated with isobutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACAD8 p.Ser98Phe (c.293C>T) in the general population?

ACAD8 p.Ser98Phe (c.293C>T) is absent from gnomAD v4.1 (gnomAD).

How is Isobutyryl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ACAD8 p.Ser98Phe (c.293C>T)?

AlphaMissense predicts ambiguous (score 0.3721) — an in-silico prediction, not a clinical call.

ACAD8 p.Ser98Phe

c.293C>T · rs948304437 · VCV468862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3721 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

isobutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.3721	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -8.68	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.076 · regional, not allelic
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACAD8
Protein: p.Ser98Phe
Coding: c.293C>T
MANE Select: NM_014384
dbSNP: rs948304437
Type: single nucleotide variant
Location: chr11:134257170 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.19 · 1 PDB

Full ACAD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Isobutyryl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACAD8 p.Ser98Pro Uncertain significance ★ ⚠ same residue
ACAD8 p.Arg206Ter Pathogenic ★★ same condition
ACAD8 p.Arg296Ter Pathogenic ★★ same condition
ACAD8 p.Gly377Ser Pathogenic/Likely pathogenic ★★ same condition
ACAD8 p.Gly96Ser Pathogenic ★★ ⚠ same condition
ACAD8 p.Met128Ile Pathogenic/Likely pathogenic ★★ same condition
ACAD8 p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
ACAD8 c.841+6A>C Uncertain significance ★★ 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/acad8-p-ser98phe (accessed [today's date]).

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