Is EARS2 p.Gln497= (c.1491A>G) pathogenic?

EARS2 p.Gln497= (c.1491A>G) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0164%, mid); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Gln497= (c.1491A>G)?

EARS2 p.Gln497= (c.1491A>G) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Gln497= (c.1491A>G) in the general population?

EARS2 p.Gln497= (c.1491A>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

EARS2 p.Gln497=

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.1491A>G · rs745678462 · VCV886035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.43	acceptor gain · deltas
Pangolin	Δ0.58	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.66	GERP 0.82, phastCons 1
Overall
CADD	19.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00267%	37,445
South Asian	0.0011%	91,086
European (non-Finnish)	0.000763%	131,103

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.Gln497=
Coding: c.1491A>G
MANE Select: NM_001083614
dbSNP: rs745678462
Type: single nucleotide variant
Location: chr16:23524452 (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-gln497 (accessed [today's date]).

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