Is EPS8 p.Asn496Ser (c.1487A>G) pathogenic?

EPS8 p.Asn496Ser (c.1487A>G) is classified Uncertain significance in EPS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0591); Ultra-rare (popmax 0.0535%, eas); Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Asn496Ser (c.1487A>G)?

EPS8 p.Asn496Ser (c.1487A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPS8 p.Asn496Ser (c.1487A>G) in the general population?

EPS8 p.Asn496Ser (c.1487A>G) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about EPS8 p.Asn496Ser (c.1487A>G)?

AlphaMissense predicts likely benign (score 0.0591) — an in-silico prediction, not a clinical call.

EPS8 p.Asn496Ser

c.1487A>G · rs750798253 · VCV1939636

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0591	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -5.56	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 -3	GERP -2.7
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	0.124	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0535% East Asian · 24/44,876 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00173% 28/1,613,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
European (non-Finnish)	0.000339%	294,973

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.Asn496Ser
Coding: c.1487A>G
MANE Select: NM_004447
dbSNP: rs750798253
Type: single nucleotide variant
Location: chr12:15647208 (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.Asn496His Uncertain significance ★ ⚠ same residue
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

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-asn496ser (accessed [today's date]).

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