Is EARS2 p.Leu357= (c.1071G>A) pathogenic?

EARS2 p.Leu357= (c.1071G>A) is classified Conflicting classifications of pathogenicity in EARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-13). Very rare (popmax 0.00267%, afr); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Leu357= (c.1071G>A)?

EARS2 p.Leu357= (c.1071G>A) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Leu357= (c.1071G>A) in the general population?

EARS2 p.Leu357= (c.1071G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

EARS2 p.Leu357=

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.1071G>A · rs769677259 · VCV318547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

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 0.34	GERP 0.64, phastCons 0.99
Overall
CADD	7.996	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,920 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,906 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,460
European (non-Finnish)	0.00127%	78,667

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.Leu357=
Coding: c.1071G>A
MANE Select: NM_001083614
dbSNP: rs769677259
Type: single nucleotide variant
Location: chr16:23529894 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84

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.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
EARS2 p.Arg361Trp 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-leu357 (accessed [today's date]).

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