Is EARS2 p.Arg108Trp (c.322C>T) pathogenic?

EARS2 p.Arg108Trp (c.322C>T) is classified Pathogenic/Likely pathogenic in EARS2 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2025-10-30). AlphaMissense: likely benign (0.1266); Ultra-rare (popmax 0.0187%, afr); Associated with EARS2-associated disorder.

What condition is associated with EARS2 p.Arg108Trp (c.322C>T)?

EARS2 p.Arg108Trp (c.322C>T) is associated with EARS2-associated disorder, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Arg108Trp (c.322C>T) in the general population?

EARS2 p.Arg108Trp (c.322C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about EARS2 p.Arg108Trp (c.322C>T)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

EARS2 p.Arg108Trp

c.322C>T · rs376103091 · VCV39787

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EARS2-associated disorder

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign ⚠ discordant with ClinVar
REVEL	0.191	benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.81, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	26.5	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 0.0187% African / African-American · 14/74,852 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0144%

Overall 0.0146% 235/1,606,474 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,347
European (non-Finnish)	0.0172%	5,830
Remaining individualsnot grpmax-eligible	0.0113%	8,881
South Asian	0.01%	9,996
Admixed American	0.00511%	19,583

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.Arg108Trp
Coding: c.322C>T
MANE Select: NM_001083614
dbSNP: rs376103091
Type: single nucleotide variant
Location: chr16:23544677 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 108: a UniProt-annotated variant site (in coxpd12)

Full EARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EARS2-associated disorder

Also linked: leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Similar variants

EARS2 p.Arg108= Likely benign ★ same residue
EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Gly317Cys 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

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-arg108trp (accessed [today's date]).

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