Is EARS2 p.Gln172Arg (c.515A>G) pathogenic?

EARS2 p.Gln172Arg (c.515A>G) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-20). AlphaMissense: likely benign (0.0655); Very rare (popmax 0.0022%, sas).

How common is EARS2 p.Gln172Arg (c.515A>G) in the general population?

EARS2 p.Gln172Arg (c.515A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EARS2 p.Gln172Arg (c.515A>G)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

EARS2 p.Gln172Arg

c.515A>G · rs753589019 · VCV1349041

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.19	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 0.12	GERP -0.78, phastCons 0.019
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	14.52	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 0.0022% South Asian · 2/90,988 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00069% 10/1,448,228 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,494
European (non-Finnish)	0.000678%	147,492

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.Gln172Arg
Coding: c.515A>G
MANE Select: NM_001083614
dbSNP: rs753589019
Type: single nucleotide variant
Location: chr16:23535331 (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

Similar variants

EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same type
EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same type
EARS2 p.Gly317Cys Pathogenic ★★ same type
EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same type
EARS2 p.Ser143Ter Pathogenic ★★ same type
EARS2 p.Ala263Thr Uncertain significance ★★ ⚠ same type
EARS2 p.Ala299Val Uncertain significance ★★ ⚠ same type

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-gln172arg (accessed [today's date]).

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