Is EARS2 p.Gly110Ser (c.328G>A) pathogenic?

EARS2 p.Gly110Ser (c.328G>A) is classified Conflicting classifications of pathogenicity in EARS2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2025-09-18). AlphaMissense: likely benign (0.3304); Ultra-rare (popmax 0.0397%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Gly110Ser (c.328G>A)?

EARS2 p.Gly110Ser (c.328G>A) is associated with Inborn genetic diseases, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

How common is EARS2 p.Gly110Ser (c.328G>A) in the general population?

EARS2 p.Gly110Ser (c.328G>A) is ultra-rare (popmax 0.0397%, nfe) (gnomAD).

What do computational predictors say about EARS2 p.Gly110Ser (c.328G>A)?

AlphaMissense predicts likely benign (score 0.3304) — an in-silico prediction, not a clinical call.

EARS2 p.Gly110Ser

c.328G>A · rs201842633 · VCV39789

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.3304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0397%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3304	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -15.47	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	29.5	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 0.0397% European (non-Finnish) · 468/1,178,140 alleles

Filtering AF 0.0367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.0308% 496/1,607,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0397%	2,517
Remaining individualsnot grpmax-eligible	0.0177%	5,655
African / African-American	0.016%	6,240
Admixed American	0.00339%	29,494
Finnishnot grpmax-eligible	0.00316%	31,644
South Asian	0.00111%	90,192

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.Gly110Ser
Coding: c.328G>A
MANE Select: NM_001083614
dbSNP: rs201842633
Type: single nucleotide variant
Location: chr16:23544671 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84
Residue 110: 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

Also linked: leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Similar variants

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.Met1Val Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Ser143Ter Pathogenic ★★ same condition
EARS2 p.Ala263Thr Uncertain significance ★★ ⚠ same condition
EARS2 p.Ala299Val Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg11Ser 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-gly110ser (accessed [today's date]).

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