Is EARS2 p.Arg107Cys (c.319C>T) pathogenic?

EARS2 p.Arg107Cys (c.319C>T) is classified Pathogenic in EARS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-14). AlphaMissense: likely benign (0.1443); Very rare (popmax 0.00512%, amr); Associated with EARS2-related disorder.

What condition is associated with EARS2 p.Arg107Cys (c.319C>T)?

EARS2 p.Arg107Cys (c.319C>T) is associated with EARS2-related disorder, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Arg107Cys (c.319C>T) in the general population?

EARS2 p.Arg107Cys (c.319C>T) is very rare (popmax 0.00512%, amr) (gnomAD).

What do computational predictors say about EARS2 p.Arg107Cys (c.319C>T)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

EARS2 p.Arg107Cys

c.319C>T · rs1355685453 · VCV973188

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00512%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EARS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign ⚠ discordant with ClinVar
REVEL	0.063	moderately benign-leaning
SaProt	LLR -11.56	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 6.4	GERP 0.87, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	25.0	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 0.00512% Admixed American · 3/58,644 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000676%

Overall 0.00081% 13/1,605,774 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00512%	19,548
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,360
East Asian	0.00224%	44,688
European (non-Finnish)	0.00068%	147,161

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.Arg107Cys
Coding: c.319C>T
MANE Select: NM_001083614
dbSNP: rs1355685453
Type: single nucleotide variant
Location: chr16:23544680 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 107: a UniProt-annotated variant site (in coxpd12)

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

Disease context

EARS2-related disorder

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

Similar variants

EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same residue
EARS2 p.Arg108Trp 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-arg107cys (accessed [today's date]).

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