Is EARS2 p.Ser422Pro (c.1264T>C) pathogenic?

EARS2 p.Ser422Pro (c.1264T>C) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.3495); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Ser422Pro (c.1264T>C)?

EARS2 p.Ser422Pro (c.1264T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Ser422Pro (c.1264T>C) in the general population?

EARS2 p.Ser422Pro (c.1264T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EARS2 p.Ser422Pro (c.1264T>C)?

AlphaMissense predicts ambiguous (score 0.3495) — an in-silico prediction, not a clinical call.

EARS2 p.Ser422Pro

c.1264T>C · VCV3843226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3495 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3495	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -11.85	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 0.59	GERP -3.7, phastCons 0.82
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	17.63	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EARS2
Protein: p.Ser422Pro
Coding: c.1264T>C
MANE Select: NM_001083614
Type: single nucleotide variant
Location: chr16:23529590 (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.Arg514Trp Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg55Cys Uncertain significance ★★ ⚠ same condition
EARS2 p.Asp182Gly 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-ser422pro (accessed [today's date]).

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