Is EARS2 p.Arg489Trp (c.1465C>T) pathogenic?

EARS2 p.Arg489Trp (c.1465C>T) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-09). AlphaMissense: likely pathogenic (0.6183); Very rare (popmax 0.00271%, nfe); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Arg489Trp (c.1465C>T)?

EARS2 p.Arg489Trp (c.1465C>T) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Arg489Trp (c.1465C>T) in the general population?

EARS2 p.Arg489Trp (c.1465C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about EARS2 p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely pathogenic (score 0.6183) — an in-silico prediction, not a clinical call.

EARS2 p.Arg489Trp

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.1465C>T · rs534853747 · VCV1978072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
AlphaMissense	0.6183	likely pathogenic
REVEL	0.657	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	32.0	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 0.00271% European (non-Finnish) · 32/1,180,030 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00223% 36/1,614,112 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,876
East Asian	0.00223%	44,886
Admixed American	0.00167%	60,010
African / African-American	0.00133%	75,012
South Asian	0.0011%	91,070

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.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_001083614
dbSNP: rs534853747
Type: single nucleotide variant
Location: chr16:23525267 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 489: 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.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-arg489trp (accessed [today's date]).

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