Is EPS8 p.Lys334Asn (c.1002G>T) pathogenic?

EPS8 p.Lys334Asn (c.1002G>T) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely pathogenic (0.9921); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Lys334Asn (c.1002G>T)?

EPS8 p.Lys334Asn (c.1002G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EPS8 p.Lys334Asn (c.1002G>T) in the general population?

EPS8 p.Lys334Asn (c.1002G>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about EPS8 p.Lys334Asn (c.1002G>T)?

AlphaMissense predicts likely pathogenic (score 0.9921) — an in-silico prediction, not a clinical call.

EPS8 p.Lys334Asn

c.1002G>T · rs773069210 · VCV2602366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9921	likely pathogenic · top 4% in EPS8
REVEL	0.496	indeterminate
SaProt	LLR -15.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -1.1, phastCons 0.97
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,846 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000342% 5/1,460,300 alleles · ultra-rare

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.Lys334Asn
Coding: c.1002G>T
MANE Select: NM_004447
dbSNP: rs773069210
Type: single nucleotide variant
Location: chr12:15658521 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 2 PDB

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-lys334asn (accessed [today's date]).

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