Is EPS8 p.Val669Met (c.2005G>A) pathogenic?

EPS8 p.Val669Met (c.2005G>A) is classified Conflicting classifications of pathogenicity in EPS8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-02). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Val669Met (c.2005G>A)?

EPS8 p.Val669Met (c.2005G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPS8 p.Val669Met (c.2005G>A) in the general population?

EPS8 p.Val669Met (c.2005G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about EPS8 p.Val669Met (c.2005G>A)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

EPS8 p.Val669Met

c.2005G>A · rs773161130 · VCV1474135

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.52	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 0.37	GERP -3.5, phastCons 0.001
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	12.9	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 0.00549% South Asian · 5/91,082 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00192% 31/1,613,902 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0156%	6,401
South Asiangrpmax	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed American	0.00333%	29,996
East Asian	0.00223%	44,892
European (non-Finnish)	0.000847%	117,997

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val669Met
Coding: c.2005G>A
MANE Select: NM_004447
dbSNP: rs773161130
Type: single nucleotide variant
Location: chr12:15631481 (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 669: the 'disordered' region; the 'effector region' region

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.Val669= Likely benign ★ 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-val669met (accessed [today's date]).

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