Is EARS2 p.Pro328Leu (c.983C>T) pathogenic?

EARS2 p.Pro328Leu (c.983C>T) is classified Uncertain significance in EARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.1212); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with EARS2 p.Pro328Leu (c.983C>T)?

EARS2 p.Pro328Leu (c.983C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EARS2 p.Pro328Leu (c.983C>T) in the general population?

EARS2 p.Pro328Leu (c.983C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about EARS2 p.Pro328Leu (c.983C>T)?

AlphaMissense predicts likely benign (score 0.1212) — an in-silico prediction, not a clinical call.

EARS2 p.Pro328Leu

c.983C>T · rs755318395 · VCV2190184

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1212	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.74, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00911% 147/1,613,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
African / African-American	0.0174%	5,761
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)	0.00983%	10,171
Finnishnot grpmax-eligible	0.00781%	12,800
East Asian	0.00446%	22,440
South Asian	0.0022%	45,509

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.Pro328Leu
Coding: c.983C>T
MANE Select: NM_001083614
dbSNP: rs755318395
Type: single nucleotide variant
Location: chr16:23532741 (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.Pro328= Benign/Likely benign ★★ 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-pro328leu (accessed [today's date]).

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