Is ETFB p.Arg21Pro (c.62G>C) pathogenic?

ETFB p.Arg21Pro (c.62G>C) is classified Uncertain significance in ETFB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.9796); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with ETFB p.Arg21Pro (c.62G>C)?

ETFB p.Arg21Pro (c.62G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ETFB p.Arg21Pro (c.62G>C) in the general population?

ETFB p.Arg21Pro (c.62G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ETFB p.Arg21Pro (c.62G>C)?

AlphaMissense predicts likely pathogenic (score 0.9796) — an in-silico prediction, not a clinical call.

ETFB p.Arg21Pro

c.62G>C · rs369216610 · VCV3090700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9796	likely pathogenic · top 10% in ETFB
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -15.45	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 4.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.9	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 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000752% 11/1,461,828 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,012
East Asian	0.00223%	44,884
European (non-Finnish)	0.000678%	147,504

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.Arg21Pro
Coding: c.62G>C
MANE Select: NM_001985
dbSNP: rs369216610
Type: single nucleotide variant
Location: chr19:51354304 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB

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.Arg21Ter Pathogenic/Likely pathogenic ★★ same residue
ETFB p.Arg21Gln Uncertain significance ★★ ⚠ same residue
ETFB p.Arg21= Likely benign ★ same residue
ETFB p.Arg21fs Pathogenic/Likely pathogenic ★★ 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

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-arg21pro (accessed [today's date]).

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