Is ETFA p.Leu154Val (c.460C>G) pathogenic?

ETFA p.Leu154Val (c.460C>G) is classified Likely benign in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0998); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with ETFA p.Leu154Val (c.460C>G)?

ETFA p.Leu154Val (c.460C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ETFA p.Leu154Val (c.460C>G) in the general population?

ETFA p.Leu154Val (c.460C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ETFA p.Leu154Val (c.460C>G)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

ETFA p.Leu154Val

c.460C>G · VCV4251289

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.7	GERP -3.7
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	0.139	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 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000436% 7/1,605,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
East Asian	0.00223%	44,810
European (non-Finnish)	0.000426%	234,518

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.Leu154Val
Coding: c.460C>G
MANE Select: NM_000126
Type: single nucleotide variant
Location: chr15:76286473 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 154: the 'domain i' region; a β-strand

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

Similar variants

ETFA p.Leu154Pro Uncertain significance ★ ⚠ same residue
ETFA p.Leu154= Likely benign ★ same residue
ETFA p.Arg169Cys Uncertain significance ★★ ⚠ same condition
ETFA p.Arg249His Uncertain significance ★★ ⚠ same condition
ETFA p.Asp174Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gln9Arg Uncertain significance ★★ ⚠ same condition
ETFA p.Glu186Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gly181Ser Uncertain significance ★★ ⚠ 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-leu154val (accessed [today's date]).

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