Is ETFB p.Pro230Leu (c.689C>T) pathogenic?

ETFB p.Pro230Leu (c.689C>T) is classified Uncertain significance in ETFB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.6301); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with ETFB p.Pro230Leu (c.689C>T)?

ETFB p.Pro230Leu (c.689C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ETFB p.Pro230Leu (c.689C>T) in the general population?

ETFB p.Pro230Leu (c.689C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about ETFB p.Pro230Leu (c.689C>T)?

AlphaMissense predicts likely pathogenic (score 0.6301) — an in-silico prediction, not a clinical call.

ETFB p.Pro230Leu

c.689C>T · VCV3846375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6301	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -14.27	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 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	27.8	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 0.00659% South Asian · 6/91,090 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.0018% 29/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,182
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,440
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.00127%	78,668

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.Pro230Leu
Coding: c.689C>T
MANE Select: NM_001985
Type: single nucleotide variant
Location: chr19:51345290 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 230: 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

Similar variants

ETFB p.Pro230= Likely benign ★★ same residue
ETFB p.Ala83Thr Uncertain significance ★★ ⚠ same condition
ETFB p.Arg174Cys Uncertain significance ★★ ⚠ same condition
ETFB p.Arg233Cys Uncertain significance ★★ ⚠ same condition
ETFB p.Arg254Gln Uncertain significance ★★ ⚠ same condition
ETFB p.Arg51Gln Uncertain significance ★★ ⚠ same condition
ETFB p.Arg76His Uncertain significance ★★ ⚠ same condition
ETFB p.Arg85Gln 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/etfb-p-pro230leu (accessed [today's date]).

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