Is ETFB p.Arg164Trp (c.490C>T) pathogenic?

ETFB p.Arg164Trp (c.490C>T) is classified Conflicting classifications of pathogenicity in ETFB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-27). AlphaMissense: likely pathogenic (0.8337); Very rare (popmax 0.0011%, sas); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFB p.Arg164Trp (c.490C>T)?

ETFB p.Arg164Trp (c.490C>T) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Arg164Trp (c.490C>T) in the general population?

ETFB p.Arg164Trp (c.490C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Multiple acyl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ETFB p.Arg164Trp (c.490C>T)?

AlphaMissense predicts likely pathogenic (score 0.8337) — an in-silico prediction, not a clinical call.

ETFB p.Arg164Trp

c.490C>T · rs148045813 · VCV1454900

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.8337	likely pathogenic
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -16.72	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 7.5	GERP 0.16, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	31.0	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 0.0011% South Asian · 1/90,664 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00186% 30/1,612,890 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0541%	1,848
Remaining individualsnot grpmax-eligible	0.0032%	31,229
South Asiangrpmax	0.0011%	90,664
European (non-Finnish)	0.000932%	107,241

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ETFB
Protein: p.Arg164Trp
Coding: c.490C>T
MANE Select: NM_001985
dbSNP: rs148045813
Type: single nucleotide variant
Location: chr19:51347007 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 164: a UniProt-annotated variant site (in ga2b; reduced electron transfer activity); a β-strand

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

Disease context

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

For Multiple acyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ETFB p.Arg164Gln Pathogenic/Likely pathogenic ★★ same residue
ETFB p.Arg164Leu Likely pathogenic ★ same residue
ETFB p.Arg164= Likely benign ★ same residue
ETFB c.375+1G>A Likely pathogenic ★★ same condition
ETFB c.375+1G>T Likely pathogenic ★★ same condition
ETFB p.Arg21Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Arg85Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Cys42Arg Pathogenic/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/etfb-p-arg164trp (accessed [today's date]).

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