Is EARS2 p.Arg55Cys (c.163C>T) pathogenic?

EARS2 p.Arg55Cys (c.163C>T) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.7126); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Arg55Cys (c.163C>T)?

EARS2 p.Arg55Cys (c.163C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Arg55Cys (c.163C>T) in the general population?

EARS2 p.Arg55Cys (c.163C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EARS2 p.Arg55Cys (c.163C>T)?

AlphaMissense predicts likely pathogenic (score 0.7126) — an in-silico prediction, not a clinical call.

EARS2 p.Arg55Cys

c.163C>T · rs1049547801 · VCV2909496

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7126	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -13.27	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000479% 7/1,461,822 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000339%	294,997

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.Arg55Cys
Coding: c.163C>T
MANE Select: NM_001083614
dbSNP: rs1049547801
Type: single nucleotide variant
Location: chr16:23552281 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 55: a UniProt-annotated variant site (in coxpd12)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EARS2 p.Arg55His Uncertain significance ★★ ⚠ same residue
EARS2 p.Ala263Thr Uncertain significance ★★ ⚠ same condition
EARS2 p.Ala299Val Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg11Ser Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg156Trp Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg166Gln Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg514Trp Uncertain significance ★★ ⚠ same condition
EARS2 p.Asp182Gly 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-arg55cys (accessed [today's date]).

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