Is ETHE1 p.Arg163= (c.489G>A) pathogenic?

ETHE1 p.Arg163= (c.489G>A) is classified Conflicting classifications of pathogenicity in ETHE1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). Rare (popmax 0.146%, sas); Associated with ethylmalonic encephalopathy.

What condition is associated with ETHE1 p.Arg163= (c.489G>A)?

ETHE1 p.Arg163= (c.489G>A) is associated with ethylmalonic encephalopathy (ClinVar).

How common is ETHE1 p.Arg163= (c.489G>A) in the general population?

ETHE1 p.Arg163= (c.489G>A) is rare (popmax 0.146%, sas) (gnomAD).

How is Ethylmalonic encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ETHE1 p.Arg163=

c.489G>A · rs533076307 · VCV765706

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.146%, sas)

Conditions

ethylmalonic encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.66	GERP -5.1, phastCons 0.015
Overall
CADD	6.306	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.146% South Asian · 133/91,090 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00886% 143/1,614,184 alleles · rare exomes 137/1,461,884 · genomes 6/152,300 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.146%	685
Remaining individualsnot grpmax-eligible	0.016%	6,251

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: ETHE1
Protein: p.Arg163=
Coding: c.489G>A
MANE Select: NM_014297
dbSNP: rs533076307
Type: single nucleotide variant
Location: chr19:43511453 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.05 · 1 PDB
Residue 163: a UniProt-annotated variant site (in ee)

Full ETHE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ethylmalonic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ethylmalonic encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ETHE1 p.Arg163Gln Pathogenic ★★★ same residue
ETHE1 p.Arg163Trp Pathogenic ★★★ same residue
ETHE1 p.Arg163Leu Likely pathogenic ★ same residue
ETHE1 c.505+1G>A Pathogenic ★★★ same condition
ETHE1 c.505+1G>T Pathogenic ★★★ same condition
ETHE1 p.Ala254Val Uncertain significance ★★★ ⚠ same condition
ETHE1 p.Arg124Leu Uncertain significance ★★★ ⚠ same condition
ETHE1 p.Lys66Arg 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/ethe1-p-arg163 (accessed [today's date]).

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