Is EARS2 p.Arg369Ser (c.1107G>T) pathogenic?

EARS2 p.Arg369Ser (c.1107G>T) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-21). AlphaMissense: ambiguous (0.5623); Very rare (popmax 0.0011%, sas).

How common is EARS2 p.Arg369Ser (c.1107G>T) in the general population?

EARS2 p.Arg369Ser (c.1107G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about EARS2 p.Arg369Ser (c.1107G>T)?

AlphaMissense predicts ambiguous (score 0.5623) — an in-silico prediction, not a clinical call.

EARS2 p.Arg369Ser

c.1107G>T · rs779595575 · VCV2175112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5623	ambiguous
REVEL	0.222	benign-leaning
SaProt	LLR -11.43	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.33	GERP 0.64, phastCons 0.026
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	11.76	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 0.0011% South Asian · 1/91,090 alleles

Overall 0.000137% 2/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,090
European (non-Finnish)	8.47e-05%	1,180,036

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.Arg369Ser
Coding: c.1107G>T
MANE Select: NM_001083614
dbSNP: rs779595575
Type: single nucleotide variant
Location: chr16:23529858 (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-arg369ser (accessed [today's date]).

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