Is EPS8 p.Arg702Trp (c.2104C>T) pathogenic?

EPS8 p.Arg702Trp (c.2104C>T) is classified Uncertain significance in EPS8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.7698); Ultra-rare (popmax 0.0569%, amr); Associated with autosomal recessive nonsyndromic hearing loss 102.

What condition is associated with EPS8 p.Arg702Trp (c.2104C>T)?

EPS8 p.Arg702Trp (c.2104C>T) is associated with autosomal recessive nonsyndromic hearing loss 102 (ClinVar).

How common is EPS8 p.Arg702Trp (c.2104C>T) in the general population?

EPS8 p.Arg702Trp (c.2104C>T) is ultra-rare (popmax 0.0569%, amr) (gnomAD).

What do computational predictors say about EPS8 p.Arg702Trp (c.2104C>T)?

AlphaMissense predicts likely pathogenic (score 0.7698) — an in-silico prediction, not a clinical call.

EPS8 p.Arg702Trp

c.2104C>T · rs201426875 · VCV1409590

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0569%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 102

Computational evidence

Protein change
AlphaMissense	0.7698	likely pathogenic
REVEL	0.215	benign-leaning
SaProt	LLR -14.26	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	31.0	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 0.0569% Admixed American · 34/59,750 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.00261% 42/1,607,834 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0569%	1,757
Remaining individualsnot grpmax-eligible	0.00161%	62,266
European (non-Finnish)	0.000595%	167,967

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: EPS8
Protein: p.Arg702Trp
Coding: c.2104C>T
MANE Select: NM_004447
dbSNP: rs201426875
Type: single nucleotide variant
Location: chr12:15624348 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 2 PDB
Residue 702: the 'effector region' region

Full EPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 102 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPS8 c.205-8A>G Uncertain significance ★★ same condition
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same condition
EPS8 p.Leu329Pro Uncertain significance ★★ ⚠ same condition
EPS8 p.Thr726Ile Uncertain significance ★★ ⚠ same condition
EPS8 p.His35Arg Benign/Likely benign ★★ same condition
EPS8 p.Ser551= Benign/Likely benign ★★ same condition
EPS8 c.1435-2A>T Likely pathogenic ★ same condition
EPS8 c.517-1G>T 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/eps8-p-arg702trp (accessed [today's date]).

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