Is EARS2 p.Glu349Val (c.1046A>T) pathogenic?

EARS2 p.Glu349Val (c.1046A>T) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2528); Ultra-rare (popmax 0.0383%, amr); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Glu349Val (c.1046A>T)?

EARS2 p.Glu349Val (c.1046A>T) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Glu349Val (c.1046A>T) in the general population?

EARS2 p.Glu349Val (c.1046A>T) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about EARS2 p.Glu349Val (c.1046A>T)?

AlphaMissense predicts likely benign (score 0.2528) — an in-silico prediction, not a clinical call.

EARS2 p.Glu349Val

c.1046A>T · rs182663883 · VCV1438575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2528 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2528	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -9.20	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 6.1	GERP 0.65, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0383% Admixed American · 23/60,010 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00198% 32/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,609
Remaining individualsnot grpmax-eligible	0.0112%	8,929
African / African-American	0.00133%	75,034
European (non-Finnish)	8.48e-05%	1,179,912

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.Glu349Val
Coding: c.1046A>T
MANE Select: NM_001083614
dbSNP: rs182663883
Type: single nucleotide variant
Location: chr16:23532678 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84

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.Glu349Lys Conflicting classifications of pathogenicity ★ ⚠ 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.Arg55Cys 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-glu349val (accessed [today's date]).

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