EARS2 p.Ala88=

Q: Is EARS2 p.Ala88= (c.264G>A) pathogenic?

EARS2 p.Ala88= (c.264G>A) is classified Benign in EARS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 81.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

Q: What condition is associated with EARS2 p.Ala88= (c.264G>A)?

EARS2 p.Ala88= (c.264G>A) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

Q: How common is EARS2 p.Ala88= (c.264G>A) in the general population?

EARS2 p.Ala88= (c.264G>A) is common (popmax 81.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.264G>A · rs7187920 · VCV137191

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 81.1%, nfe) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.4
Overall
CADD	0.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 81.1% European (non-Finnish) · 957,378/1,179,890 alleles

Filtering AF 81% ClinGen BA1/BS1 input FAF95, joint · FAF99 80.9%

Overall 78.4% 1,265,560/1,613,726 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	83.8%	1
European (non-Finnish)grpmax	81.1%	1
Ashkenazi Jewishnot grpmax-eligible	78.7%	1
Remaining individualsnot grpmax-eligible	76.9%	1
Middle Eastern	75.8%	1
Finnishnot grpmax-eligible	75.4%	1
Admixed American	74.6%	1
South Asian	71.6%	1
East Asian	68%	1
African / African-American	57.1%	2

Amish 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: EARS2
Protein: p.Ala88=
Coding: c.264G>A
MANE Select: NM_001083614
dbSNP: rs7187920
Type: single nucleotide variant
Location: chr16:23552180 (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.Ala88Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
EARS2 p.Ala88Val 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

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-ala88 (accessed [today's date]).

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