Is ETFB p.Pro40Thr (c.118C>A) pathogenic?

ETFB p.Pro40Thr (c.118C>A) is classified Uncertain significance in ETFB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-30). AlphaMissense: likely pathogenic (0.9213); Very rare (popmax 0.00686%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ETFB p.Pro40Thr (c.118C>A)?

ETFB p.Pro40Thr (c.118C>A) is associated with Inborn genetic diseases, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Pro40Thr (c.118C>A) in the general population?

ETFB p.Pro40Thr (c.118C>A) is very rare (popmax 0.00686%, nfe) (gnomAD).

What do computational predictors say about ETFB p.Pro40Thr (c.118C>A)?

AlphaMissense predicts likely pathogenic (score 0.9213) — an in-silico prediction, not a clinical call.

ETFB p.Pro40Thr

c.118C>A · rs772322071 · VCV969573

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9213	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -14.76	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 9.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00686% European (non-Finnish) · 81/1,180,038 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00514% 83/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00686%	14,568
Admixed American	0.00167%	59,998
African / African-American	0.00133%	74,916

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.Pro40Thr
Coding: c.118C>A
MANE Select: NM_001985
dbSNP: rs772322071
Type: single nucleotide variant
Location: chr19:51354248 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 40: 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-pro40thr (accessed [today's date]).

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