Is ETFA p.Gly181Ser (c.541G>A) pathogenic?

ETFA p.Gly181Ser (c.541G>A) is classified Uncertain significance in ETFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1531); Very rare (popmax 0.00668%, afr); Associated with Inborn genetic diseases.

What condition is associated with ETFA p.Gly181Ser (c.541G>A)?

ETFA p.Gly181Ser (c.541G>A) is associated with Inborn genetic diseases, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Gly181Ser (c.541G>A) in the general population?

ETFA p.Gly181Ser (c.541G>A) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about ETFA p.Gly181Ser (c.541G>A)?

AlphaMissense predicts likely benign (score 0.1531) — an in-silico prediction, not a clinical call.

ETFA p.Gly181Ser

c.541G>A · rs374127169 · VCV989856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1531	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.7	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 0.00668% African / African-American · 5/74,900 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00304% 49/1,611,640 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,980
European (non-Finnish)	0.0034%	29,449
Admixed American	0.00334%	29,983
South Asian	0.0022%	45,486

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.Gly181Ser
Coding: c.541G>A
MANE Select: NM_000126
dbSNP: rs374127169
Type: single nucleotide variant
Location: chr15:76286392 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 181: the 'domain i' region

Full ETFA 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

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-gly181ser (accessed [today's date]).

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