Is EARS2 p.Phe293Ser (c.878T>C) pathogenic?

EARS2 p.Phe293Ser (c.878T>C) is classified Conflicting classifications of pathogenicity in EARS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.3767); Rare (popmax 0.109%, afr); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Phe293Ser (c.878T>C)?

EARS2 p.Phe293Ser (c.878T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Phe293Ser (c.878T>C) in the general population?

EARS2 p.Phe293Ser (c.878T>C) is rare (popmax 0.109%, afr) (gnomAD).

What do computational predictors say about EARS2 p.Phe293Ser (c.878T>C)?

AlphaMissense predicts ambiguous (score 0.3767) — an in-silico prediction, not a clinical call.

EARS2 p.Phe293Ser

c.878T>C · rs201279526 · VCV1204048

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3767 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3767	ambiguous
REVEL	0.439	indeterminate
SaProt	LLR -4.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	23.4	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 0.109% African / African-American · 82/75,032 alleles

Filtering AF 0.0902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0831%

Overall 0.00614% 99/1,611,748 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.109%	915
Middle Eastern	0.0171%	5,846
Remaining individualsnot grpmax-eligible	0.0144%	6,930
Admixed American	0.01%	9,983
European (non-Finnish)	8.49e-05%	1,178,423

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.Phe293Ser
Coding: c.878T>C
MANE Select: NM_001083614
dbSNP: rs201279526
Type: single nucleotide variant
Location: chr16:23534968 (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.Phe293Leu Uncertain significance ★ ⚠ same residue
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

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-phe293ser (accessed [today's date]).

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