Is ETHE1 p.Ser93Phe (c.278C>T) pathogenic?

ETHE1 p.Ser93Phe (c.278C>T) is classified Uncertain significance in ETHE1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.2616); Rare (popmax 0.137%, amr); Associated with ethylmalonic encephalopathy.

What condition is associated with ETHE1 p.Ser93Phe (c.278C>T)?

ETHE1 p.Ser93Phe (c.278C>T) is associated with ethylmalonic encephalopathy (ClinVar).

How common is ETHE1 p.Ser93Phe (c.278C>T) in the general population?

ETHE1 p.Ser93Phe (c.278C>T) is rare (popmax 0.137%, amr) (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.Ser93Phe (c.278C>T)?

AlphaMissense predicts likely benign (score 0.2616) — an in-silico prediction, not a clinical call.

ETHE1 p.Ser93Phe

c.278C>T · rs199827754 · VCV214324

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2616 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.137%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ethylmalonic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.2616	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -13.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 20 kb · p 0.066 · regional, not allelic
Overall
CADD	28.6	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 0.137% Admixed American · 82/59,990 alleles

Filtering AF 0.113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.0257% 415/1,614,002 alleles · rare exomes 369/1,461,854 · genomes 46/152,148 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.152%	658
Admixed Americangrpmax	0.137%	732
Middle Eastern	0.0657%	1,521
Remaining individualsnot grpmax-eligible	0.0592%	1,689
South Asian	0.0549%	1,822
European (non-Finnish)	0.0165%	6,051
African / African-American	0.00267%	37,457

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser93Phe
Coding: c.278C>T
MANE Select: NM_014297
dbSNP: rs199827754
Type: single nucleotide variant
Location: chr19:43526298 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.05 · 1 PDB
Residue 93: an α-helix

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.Ser93Tyr 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-ser93phe (accessed [today's date]).

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