Is EPS8L2 p.Pro308Ser (c.922C>T) pathogenic?

EPS8L2 p.Pro308Ser (c.922C>T) is classified Uncertain significance in EPS8L2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-03). AlphaMissense: ambiguous (0.4397); Ultra-rare (popmax 0.0137%, eas); Associated with Meniere disease.

What condition is associated with EPS8L2 p.Pro308Ser (c.922C>T)?

EPS8L2 p.Pro308Ser (c.922C>T) is associated with Meniere disease (ClinVar).

How common is EPS8L2 p.Pro308Ser (c.922C>T) in the general population?

EPS8L2 p.Pro308Ser (c.922C>T) is ultra-rare (popmax 0.0137%, eas) (gnomAD).

What do computational predictors say about EPS8L2 p.Pro308Ser (c.922C>T)?

AlphaMissense predicts ambiguous (score 0.4397) — an in-silico prediction, not a clinical call.

EPS8L2 p.Pro308Ser

c.922C>T · rs557789113 · VCV3238940

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4397 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Meniere disease

Computational evidence

Protein change
AlphaMissense	0.4397	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -11.47	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 5.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 18 kb · p 2.2e-09 · regional, not allelic
Overall
CADD	27.5	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 0.0137% East Asian · 6/43,670 alleles

Filtering AF 0.00592% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.000439% 7/1,595,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0137%	7,278
Remaining individualsnot grpmax-eligible	0.00162%	61,744

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: EPS8L2
Protein: p.Pro308Ser
Coding: c.922C>T
MANE Select: NM_022772
dbSNP: rs557789113
Type: single nucleotide variant
Location: chr11:721929 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 2 PDB

Full EPS8L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meniere disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPS8L2 p.Pro308= Benign ★★ same residue
EPS8L2 p.Arg272Trp Uncertain significance ★★ ⚠ same condition
EPS8L2 p.Gly5Arg Uncertain significance ★★ ⚠ same condition
EPS8L2 p.Arg381Cys Uncertain significance ⚠ same condition
EPS8L2 p.Phe269Leu Uncertain significance ⚠ same condition
EPS8L2 p.Glu165Ter Likely pathogenic ★★ same type
EPS8L2 p.Arg102Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg193Gln 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/eps8l2-p-pro308ser (accessed [today's date]).

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