Is ETHE1 p.Ser45= (c.135C>T) pathogenic?

ETHE1 p.Ser45= (c.135C>T) is classified Likely benign in ETHE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). Very rare (popmax 0.00133%, afr); Associated with ethylmalonic encephalopathy.

What condition is associated with ETHE1 p.Ser45= (c.135C>T)?

ETHE1 p.Ser45= (c.135C>T) is associated with ethylmalonic encephalopathy (ClinVar).

How common is ETHE1 p.Ser45= (c.135C>T) in the general population?

ETHE1 p.Ser45= (c.135C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Ethylmalonic encephalopathy inherited?

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

ETHE1 p.Ser45=

c.135C>T · rs1972254325 · VCV2836805

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

ethylmalonic encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.012	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.013	GERP -0.98, phastCons 0.045
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,022 alleles

Overall 0.000124% 2/1,614,090 alleles · very rare exomes 2/1,461,836 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,022
European (non-Finnish)	8.47e-05%	1,180,011

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.Ser45=
Coding: c.135C>T
MANE Select: NM_014297
dbSNP: rs1972254325
Type: single nucleotide variant
Location: chr19:43526606 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.05 · 1 PDB
Residue 45: a turn

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 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
ETHE1 p.Val143Ile 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-ser45 (accessed [today's date]).

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