Is EARS2 p.Cys142Ser (c.425G>C) pathogenic?

EARS2 p.Cys142Ser (c.425G>C) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9743); Absent from gnomAD v4.1; Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Cys142Ser (c.425G>C)?

EARS2 p.Cys142Ser (c.425G>C) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Cys142Ser (c.425G>C) in the general population?

EARS2 p.Cys142Ser (c.425G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EARS2 p.Cys142Ser (c.425G>C)?

AlphaMissense predicts likely pathogenic (score 0.9743) — an in-silico prediction, not a clinical call.

EARS2 p.Cys142Ser

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.425G>C · VCV4852410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9743 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
AlphaMissense	0.9743	likely pathogenic · top 5% in EARS2
REVEL	0.541	indeterminate
SaProt	LLR -14.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EARS2
Protein: p.Cys142Ser
Coding: c.425G>C
MANE Select: NM_001083614
Type: single nucleotide variant
Location: chr16:23544574 (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-cys142ser (accessed [today's date]).

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