Is EARS2 p.Arg516Gln (c.1547G>A) pathogenic?

EARS2 p.Arg516Gln (c.1547G>A) is classified Conflicting classifications of pathogenicity in EARS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.701); Very rare (popmax 0.01%, nfe); Associated with EARS2-related disorder.

What condition is associated with EARS2 p.Arg516Gln (c.1547G>A)?

EARS2 p.Arg516Gln (c.1547G>A) is associated with EARS2-related disorder, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Arg516Gln (c.1547G>A) in the general population?

EARS2 p.Arg516Gln (c.1547G>A) is very rare (popmax 0.01%, nfe) (gnomAD).

What do computational predictors say about EARS2 p.Arg516Gln (c.1547G>A)?

AlphaMissense predicts likely pathogenic (score 0.701) — an in-silico prediction, not a clinical call.

EARS2 p.Arg516Gln

c.1547G>A · rs201727231 · VCV265109

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EARS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.701	likely pathogenic
REVEL	0.546	indeterminate
SaProt	LLR -11.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	28.7	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 0.01% European (non-Finnish) · 118/1,180,022 alleles

Filtering AF 0.00851% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00795%

Overall 0.00768% 124/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00167%	59,992
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	74,928

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.Arg516Gln
Coding: c.1547G>A
MANE Select: NM_001083614
dbSNP: rs201727231
Type: single nucleotide variant
Location: chr16:23524396 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 516: 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.Arg516Gly Uncertain significance ★★ ⚠ same residue
EARS2 p.Arg516Trp Uncertain significance ★ ⚠ same residue
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.Gly317Cys Pathogenic ★★ same condition
EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Ser143Ter Pathogenic ★★ 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-arg516gln (accessed [today's date]).

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