Is EARS2 p.Arg514Trp (c.1540C>T) pathogenic?

EARS2 p.Arg514Trp (c.1540C>T) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1196); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Arg514Trp (c.1540C>T)?

EARS2 p.Arg514Trp (c.1540C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Arg514Trp (c.1540C>T) in the general population?

EARS2 p.Arg514Trp (c.1540C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about EARS2 p.Arg514Trp (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

EARS2 p.Arg514Trp

c.1540C>T · rs376807600 · VCV2302440

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -8.78	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 4.5	GERP -0.21, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	18.57	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 0.0143% South Asian · 13/91,088 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00359% 58/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
South Asiangrpmax	0.0143%	7,007
Remaining individualsnot grpmax-eligible	0.008%	12,497
East Asian	0.00668%	14,965
European (non-Finnish)	0.00237%	42,144
African / African-American	0.00133%	74,916

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg514Trp
Coding: c.1540C>T
MANE Select: NM_001083614
dbSNP: rs376807600
Type: single nucleotide variant
Location: chr16:23524403 (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.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.Arg55Cys Uncertain significance ★★ ⚠ same condition
EARS2 p.Asp182Gly Uncertain significance ★★ ⚠ same condition
EARS2 p.Glu349Val 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-arg514trp (accessed [today's date]).

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