Is ACAD8 p.Phe136= (c.408C>T) pathogenic?

ACAD8 p.Phe136= (c.408C>T) is classified Benign/Likely benign in ACAD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-27). Ultra-rare (popmax 0.0165%, mid); Associated with isobutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACAD8 p.Phe136= (c.408C>T)?

ACAD8 p.Phe136= (c.408C>T) is associated with isobutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACAD8 p.Phe136= (c.408C>T) in the general population?

ACAD8 p.Phe136= (c.408C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Isobutyryl-CoA dehydrogenase deficiency inherited?

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

ACAD8 p.Phe136=

c.408C>T · rs143408080 · VCV741347

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

isobutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	acceptor loss, 27 bp away · masked 0 · deltas
Pangolin	Δ0.29	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.042	GERP -2.8, phastCons 0.91
Overall
CADD	7.206	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00905% 146/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.0147%	6,815
Remaining individualsnot grpmax-eligible	0.0112%	8,928
European (non-Finnish)	0.0102%	9,832
East Asian	0.00669%	14,957
Admixed American	0.00333%	29,999
South Asian	0.0022%	45,511

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: ACAD8
Protein: p.Phe136=
Coding: c.408C>T
MANE Select: NM_014384
dbSNP: rs143408080
Type: single nucleotide variant
Location: chr11:134258542 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.19 · 1 PDB
Residue 136: an α-helix

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.Phe136Leu 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-phe136 (accessed [today's date]).

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