Is EARS2 p.Glu96Lys (c.286G>A) pathogenic?

EARS2 p.Glu96Lys (c.286G>A) is classified Pathogenic in EARS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-04). AlphaMissense: likely benign (0.2333); Very rare (popmax 0.00167%, amr); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Glu96Lys (c.286G>A)?

EARS2 p.Glu96Lys (c.286G>A) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Glu96Lys (c.286G>A) in the general population?

EARS2 p.Glu96Lys (c.286G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EARS2 p.Glu96Lys (c.286G>A)?

AlphaMissense predicts likely benign (score 0.2333) — an in-silico prediction, not a clinical call.

EARS2 p.Glu96Lys

Q: How is Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome inherited?

Typically No data available (Orphanet). A genetic counselor can assess individual risk for a family.

c.286G>A · rs397514593 · VCV39791

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
AlphaMissense	0.2333	likely benign ⚠ discordant with ClinVar
REVEL	0.103	moderately benign-leaning
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	24.0	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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,536 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.00017%	589,904

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: EARS2
Protein: p.Glu96Lys
Coding: c.286G>A
MANE Select: NM_001083614
dbSNP: rs397514593
Type: single nucleotide variant
Location: chr16:23552158 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 96: a UniProt-annotated variant site (in coxpd12)

Full EARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (Orphanet):

Inheritance: No data available
Onset: Infancy, Neonatal

Similar variants

EARS2 p.Glu96Gln Uncertain significance ★ ⚠ same residue
EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Ser143Ter Pathogenic ★★ same condition
EARS2 p.Arg162Trp Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg188His 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/ears2-p-glu96lys (accessed [today's date]).

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