Is ETFB p.Pro93Leu (c.278C>T) pathogenic?

ETFB p.Pro93Leu (c.278C>T) is classified Conflicting classifications of pathogenicity in ETFB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0367%, amr); Associated with Inborn genetic diseases.

What condition is associated with ETFB p.Pro93Leu (c.278C>T)?

ETFB p.Pro93Leu (c.278C>T) is associated with Inborn genetic diseases, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Pro93Leu (c.278C>T) in the general population?

ETFB p.Pro93Leu (c.278C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about ETFB p.Pro93Leu (c.278C>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

ETFB p.Pro93Leu

c.278C>T · rs139519507 · VCV203696

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	15.26	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 0.0367% Admixed American · 22/60,022 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.0237% 382/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Middle Eastern	0.033%	3,030
Finnishnot grpmax-eligible	0.0313%	3,195
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.0262%	3,819
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
African / African-American	0.00666%	15,007
South Asian	0.00329%	30,362

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.Pro93Leu
Coding: c.278C>T
MANE Select: NM_001985
dbSNP: rs139519507
Type: single nucleotide variant
Location: chr19:51353229 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 93: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple acyl-CoA dehydrogenase deficiency

Similar variants

ETFB c.375+1G>A Likely pathogenic ★★ same condition
ETFB c.375+1G>T Likely pathogenic ★★ same condition
ETFB p.Arg164Gln Pathogenic/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
ETFB p.Gln136Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Glu60Ter 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-pro93leu (accessed [today's date]).

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