Is EARS2 c.*91C>T pathogenic?

EARS2 c.91C>T is classified Likely benign in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Rare (popmax 0.455%, afr); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

How common is EARS2 c.*91C>T in the general population?

EARS2 c.*91C>T is rare (popmax 0.455%, afr) (gnomAD).

EARS2 c.*91C>T

Q: What condition is associated with EARS2 c.*91C>T?

EARS2 c.*91C>T is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

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.

rs141499212 · VCV885123

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.455%, 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 -3	GERP -2.8
Overall
CADD	2.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.455% African / African-American · 294/64,574 alleles

Filtering AF 0.413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.396%

Overall 0.0315% 347/1,102,394 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.455%	220
Admixed American	0.0339%	2,953
Remaining individualsnot grpmax-eligible	0.0286%	3,495
European (non-Finnish)	0.00291%	34,309

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
Coding: c.*91C>T
MANE Select: NM_001083614
dbSNP: rs141499212
Type: single nucleotide variant
Location: chr16:23524280 (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-c-star-91c-t (accessed [today's date]).

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