Is EPS8 p.Arg66His (c.197G>A) pathogenic?

EPS8 p.Arg66His (c.197G>A) is classified Conflicting classifications of pathogenicity in EPS8 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.0687); Rare (popmax 0.628%, mid); Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Arg66His (c.197G>A)?

EPS8 p.Arg66His (c.197G>A) is associated with Inborn genetic diseases, autosomal recessive nonsyndromic hearing loss 102 (ClinVar).

How common is EPS8 p.Arg66His (c.197G>A) in the general population?

EPS8 p.Arg66His (c.197G>A) is rare (popmax 0.628%, mid) (gnomAD).

What do computational predictors say about EPS8 p.Arg66His (c.197G>A)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

EPS8 p.Arg66His

c.197G>A · rs77383735 · VCV1207459

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.628%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -9.99	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 2.3	GERP 0.6, phastCons 0.98
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	18.43	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 0.628% Middle Eastern · 38/6,050 alleles

Filtering AF 0.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.416%

Overall 0.068% 1,092/1,606,960 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.628%	159
Admixed American	0.124%	807
Remaining individualsnot grpmax-eligible	0.0948%	1,055
European (non-Finnish)	0.0725%	1,379
South Asian	0.0575%	1,740
African / African-American	0.0174%	5,759
Finnishnot grpmax-eligible	0.00626%	15,985

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.Arg66His
Coding: c.197G>A
MANE Select: NM_004447
dbSNP: rs77383735
Type: single nucleotide variant
Location: chr12:15670863 (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 66: the ptb domain

Full EPS8 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

Also linked: autosomal recessive nonsyndromic hearing loss 102

Similar variants

EPS8 p.Arg66Gly Uncertain significance ★ ⚠ same residue
EPS8 c.205-8A>G Uncertain significance ★★ same condition
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same condition
EPS8 p.Ala416Asp Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg195Trp Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg403Trp Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg432Gln Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg434Cys 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/eps8-p-arg66his (accessed [today's date]).

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