Is EARS2 p.Pro43Ser (c.127C>T) pathogenic?

EARS2 p.Pro43Ser (c.127C>T) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-27). AlphaMissense: likely pathogenic (0.9522); Very rare (popmax 0.000263%, nfe).

How common is EARS2 p.Pro43Ser (c.127C>T) in the general population?

EARS2 p.Pro43Ser (c.127C>T) is very rare (popmax 0.000263%, nfe) (gnomAD).

What do computational predictors say about EARS2 p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely pathogenic (score 0.9522) — an in-silico prediction, not a clinical call.

EARS2 p.Pro43Ser

c.127C>T · rs1226228932 · VCV1964850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000263%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9522	likely pathogenic · top 9% in EARS2
REVEL	0.73	pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 22 kb · p 0.014 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000263% European (non-Finnish) · 3/1,140,692 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000198% 3/1,516,156 alleles · very rare exomes 2/1,363,944 · genomes 1/152,212 · joint denominator

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.Pro43Ser
Coding: c.127C>T
MANE Select: NM_001083614
dbSNP: rs1226228932
Type: single nucleotide variant
Location: chr16:23557217 (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-pro43ser (accessed [today's date]).

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