Is ETHE1 p.Arg16= (c.48C>G) pathogenic?

ETHE1 p.Arg16= (c.48C>G) is classified Likely benign in ETHE1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-06-30). Very rare (popmax 0.00704%, sas); Associated with ethylmalonic encephalopathy.

What condition is associated with ETHE1 p.Arg16= (c.48C>G)?

ETHE1 p.Arg16= (c.48C>G) is associated with ethylmalonic encephalopathy (ClinVar).

How common is ETHE1 p.Arg16= (c.48C>G) in the general population?

ETHE1 p.Arg16= (c.48C>G) is very rare (popmax 0.00704%, sas) (gnomAD).

How is Ethylmalonic encephalopathy inherited?

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

ETHE1 p.Arg16=

c.48C>G · rs775755606 · VCV797587

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00704%, 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 0.3	GERP -1.1
Overall
CADD	5.484	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00704% South Asian · 6/85,202 alleles

Filtering AF 0.00303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000386% 6/1,554,950 alleles · very rare exomes 4/1,402,708 · genomes 2/152,242 · joint denominator

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.Arg16=
Coding: c.48C>G
MANE Select: NM_014297
dbSNP: rs775755606
Type: single nucleotide variant
Location: chr19:43527130 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.05 · 1 PDB

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.Arg16Cys Uncertain significance ★★ ⚠ same residue
ETHE1 c.505+1G>A Pathogenic ★★★ same condition
ETHE1 c.505+1G>T Pathogenic ★★★ same condition
ETHE1 p.Arg163Gln Pathogenic ★★★ same condition
ETHE1 p.Arg163Trp 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-arg16 (accessed [today's date]).

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