Is ETFA p.Thr178Arg (c.533C>G) pathogenic?

ETFA p.Thr178Arg (c.533C>G) is classified Conflicting classifications of pathogenicity in ETFA (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.146); Ultra-rare (popmax 0.0505%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Thr178Arg (c.533C>G)?

ETFA p.Thr178Arg (c.533C>G) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Thr178Arg (c.533C>G) in the general population?

ETFA p.Thr178Arg (c.533C>G) is ultra-rare (popmax 0.0505%, nfe) (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 ETFA p.Thr178Arg (c.533C>G)?

AlphaMissense predicts likely benign (score 0.146) — an in-silico prediction, not a clinical call.

ETFA p.Thr178Arg

c.533C>G · rs140169311 · VCV203687

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.146	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	19.17	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 0.0505% European (non-Finnish) · 595/1,179,154 alleles

Filtering AF 0.0471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0457%

Overall 0.05% 807/1,613,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.283%	354
European (non-Finnish)grpmax	0.0505%	1,982
Remaining individualsnot grpmax-eligible	0.0224%	4,461
Admixed American	0.0183%	5,453
Middle Eastern	0.0164%	6,084
African / African-American	0.00534%	18,726
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592

Finnish 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: ETFA
Protein: p.Thr178Arg
Coding: c.533C>G
MANE Select: NM_000126
dbSNP: rs140169311
Type: single nucleotide variant
Location: chr15:76286400 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 178: the 'domain i' region; a β-strand

Full ETFA 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

ETFA c.186+1G>A Likely pathogenic ★★ same condition
ETFA c.39+1G>A Likely pathogenic ★★ same condition
ETFA c.451+1G>A Likely pathogenic ★★ same condition
ETFA c.452-2A>G Likely pathogenic ★★ same condition
ETFA c.664+1G>A Likely pathogenic ★★ same condition
ETFA c.665-1G>A Likely pathogenic ★★ same condition
ETFA p.Arg122Lys Likely pathogenic ★★ same condition
ETFA p.Arg18Ter 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/etfa-p-thr178arg (accessed [today's date]).

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