Is EARS2 p.Ser457Gly (c.1369A>G) pathogenic?

EARS2 p.Ser457Gly (c.1369A>G) is classified Benign in EARS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0625); Common (popmax 88.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

What condition is associated with EARS2 p.Ser457Gly (c.1369A>G)?

EARS2 p.Ser457Gly (c.1369A>G) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

What do computational predictors say about EARS2 p.Ser457Gly (c.1369A>G)?

AlphaMissense predicts likely benign (score 0.0625) — an in-silico prediction, not a clinical call.

EARS2 p.Ser457Gly

Q: How common is EARS2 p.Ser457Gly (c.1369A>G) in the general population?

EARS2 p.Ser457Gly (c.1369A>G) is common (popmax 88.3%, mid) — 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.1369A>G · rs6497671 · VCV137186

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0625 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 88.3%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
AlphaMissense	0.0625	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.02	GERP -3
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	0.301	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 88.3% Middle Eastern · 5,351/6,060 alleles

Filtering AF 86.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.5%

Overall 84.3% 1,359,469/1,613,500 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	89.5%	1
Middle Easterngrpmax	88.3%	1
Admixed American	85.6%	1
European (non-Finnish)	85.3%	1
Amishnot grpmax-eligible	85.2%	1
Remaining individualsnot grpmax-eligible	83.9%	1
African / African-American	83.3%	1
South Asian	79.7%	1
Finnishnot grpmax-eligible	78.4%	1
East Asian	69.6%	1

Ashkenazi Jewish 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.Ser457Gly
Coding: c.1369A>G
MANE Select: NM_001083614
dbSNP: rs6497671
Type: single nucleotide variant
Location: chr16:23525363 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 457: a UniProt-annotated variant site (in)

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-ser457gly (accessed [today's date]).

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