Is EPS8 p.His35Arg (c.104A>G) pathogenic?

EPS8 p.His35Arg (c.104A>G) is classified Benign/Likely benign in EPS8 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0681); Low-frequency (popmax 1.19%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 102.

How common is EPS8 p.His35Arg (c.104A>G) in the general population?

EPS8 p.His35Arg (c.104A>G) is low-frequency (popmax 1.19%, nfe) (gnomAD).

What do computational predictors say about EPS8 p.His35Arg (c.104A>G)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

EPS8 p.His35Arg

Q: What condition is associated with EPS8 p.His35Arg (c.104A>G)?

EPS8 p.His35Arg (c.104A>G) is associated with autosomal recessive nonsyndromic hearing loss 102, hearing loss, autosomal recessive 106 (ClinVar).

c.104A>G · rs71532816 · VCV508700

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 102

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.64	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 4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	17.57	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 1.19% European (non-Finnish) · 13,686/1,151,084 alleles

Filtering AF 1.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.17%

Overall 0.94% 14,721/1,566,758 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.19%	84
Remaining individualsnot grpmax-eligible	0.684%	146
Finnishnot grpmax-eligible	0.386%	259
Admixed American	0.298%	335
African / African-American	0.189%	530
Middle Eastern	0.0879%	1,138
South Asian	0.0747%	1,339
Ashkenazi Jewishnot grpmax-eligible	0.0139%	7,171
East Asian	0.00232%	43,066

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.His35Arg
Coding: c.104A>G
MANE Select: NM_004447
dbSNP: rs71532816
Type: single nucleotide variant
Location: chr12:15681258 (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 35: the 'disordered' 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

Also linked: hearing loss, autosomal recessive 106

Similar variants

EPS8 c.205-8A>G Uncertain significance ★★ same condition
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg702Trp Uncertain significance ★★ ⚠ same condition
EPS8 p.Leu329Pro Uncertain significance ★★ ⚠ same condition
EPS8 p.Thr726Ile Uncertain significance ★★ ⚠ 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-his35arg (accessed [today's date]).

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