Is EPS8 p.Leu93Trp (c.278T>G) pathogenic?

EPS8 p.Leu93Trp (c.278T>G) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: likely pathogenic (0.8005); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Leu93Trp (c.278T>G)?

EPS8 p.Leu93Trp (c.278T>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPS8 p.Leu93Trp (c.278T>G) in the general population?

EPS8 p.Leu93Trp (c.278T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPS8 p.Leu93Trp (c.278T>G)?

AlphaMissense predicts likely pathogenic (score 0.8005) — an in-silico prediction, not a clinical call.

EPS8 p.Leu93Trp

c.278T>G · VCV4250252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8005 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8005	likely pathogenic
REVEL	0.266	benign-leaning
SaProt	LLR -11.56	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	27.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPS8
Protein: p.Leu93Trp
Coding: c.278T>G
MANE Select: NM_004447
Type: single nucleotide variant
Location: chr12:15669752 (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 93: 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

Similar variants

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
EPS8 p.Arg597Cys Uncertain significance ★★ ⚠ same condition
EPS8 p.Arg597Ser 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-leu93trp (accessed [today's date]).

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