Is ETHE1 p.Ser203Phe (c.608C>T) pathogenic?

ETHE1 p.Ser203Phe (c.608C>T) is classified Conflicting classifications of pathogenicity in ETHE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-12). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 0.00331%, nfe); Associated with ethylmalonic encephalopathy.

What condition is associated with ETHE1 p.Ser203Phe (c.608C>T)?

ETHE1 p.Ser203Phe (c.608C>T) is associated with ethylmalonic encephalopathy (ClinVar).

How common is ETHE1 p.Ser203Phe (c.608C>T) in the general population?

ETHE1 p.Ser203Phe (c.608C>T) is very rare (popmax 0.00331%, nfe) (gnomAD).

How is Ethylmalonic encephalopathy inherited?

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

What do computational predictors say about ETHE1 p.Ser203Phe (c.608C>T)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

ETHE1 p.Ser203Phe

c.608C>T · rs267605525 · VCV2152318

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ethylmalonic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic · top 2% in ETHE1
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -15.23	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 20 kb · p 0.066 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% European (non-Finnish) · 39/1,180,002 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00242% 39/1,613,860 alleles · very rare exomes 38/1,461,696 · genomes 1/152,164 · 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.Ser203Phe
Coding: c.608C>T
MANE Select: NM_014297
dbSNP: rs267605525
Type: single nucleotide variant
Location: chr19:43508048 (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.Ser203= Likely benign ★ 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-ser203phe (accessed [today's date]).

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