Is EPS8L2 p.Pro471fs (c.1412del) pathogenic?

EPS8L2 p.Pro471fs (c.1412del) is classified Likely pathogenic in EPS8L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). Very rare (popmax 0.00934%, eas); Associated with hearing loss, autosomal recessive 106.

What condition is associated with EPS8L2 p.Pro471fs (c.1412del)?

EPS8L2 p.Pro471fs (c.1412del) is associated with hearing loss, autosomal recessive 106 (ClinVar).

How common is EPS8L2 p.Pro471fs (c.1412del) in the general population?

EPS8L2 p.Pro471fs (c.1412del) is very rare (popmax 0.00934%, eas) (gnomAD).

EPS8L2 p.Pro471fs

c.1412del · VCV4687936

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00934%, eas)

Conditions

hearing loss, autosomal recessive 106

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.68	GERP -0.071

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% East Asian · 4/42,842 alleles

Filtering AF 0.00341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00222% 32/1,443,308 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00934%	10,711
Admixed American	0.00884%	11,318
South Asian	0.00565%	17,714
Remaining individualsnot grpmax-eligible	0.00163%	61,468
Finnishnot grpmax-eligible	0.00159%	62,956
European (non-Finnish)	0.00137%	73,178

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.Pro471fs
Coding: c.1412del
MANE Select: NM_022772
Type: Deletion
Location: chr11:723305 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 2 PDB
Residue 471: the 'disordered' region

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

Disease context

hearing loss, autosomal recessive 106 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPS8L2 p.Pro471Leu Benign/Likely benign ★★ same residue
EPS8L2 p.Lys333fs Pathogenic ★ same condition
EPS8L2 p.Ser339fs Pathogenic ★ same condition
EPS8L2 p.Pro471= Conflicting classifications of pathogenicity ★ same residue
EPS8L2 p.Pro471Arg Uncertain significance ★ ⚠ same residue
EPS8L2 p.Val247fs Pathogenic same condition
EPS8L2 p.Asp473fs Pathogenic ★★ same condition
EPS8L2 p.Val478fs Pathogenic/Likely pathogenic ★★ 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/eps8l2-p-pro471fs (accessed [today's date]).

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