Is EPS8 p.Val224Ile (c.670G>A) pathogenic?

EPS8 p.Val224Ile (c.670G>A) is classified Conflicting classifications of pathogenicity in EPS8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0329%, mid).

How common is EPS8 p.Val224Ile (c.670G>A) in the general population?

EPS8 p.Val224Ile (c.670G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about EPS8 p.Val224Ile (c.670G>A)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

EPS8 p.Val224Ile

c.670G>A · rs758506896 · VCV666692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.23	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 0.38	GERP -0.31, phastCons 0.026
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	11.46	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00762% 123/1,613,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
Admixed American	0.0184%	5,440
South Asian	0.0165%	6,068
African / African-American	0.00935%	10,700
East Asian	0.00891%	11,218
European (non-Finnish)	0.00678%	14,747
Remaining individualsnot grpmax-eligible	0.0064%	15,616

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.Val224Ile
Coding: c.670G>A
MANE Select: NM_004447
dbSNP: rs758506896
Type: single nucleotide variant
Location: chr12:15665822 (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 224: the 'disordered' region

Full EPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8 c.205-8A>G Uncertain significance ★★ same type
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala219Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala416Asp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg195Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg403Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg432Gln Uncertain significance ★★ ⚠ same type
EPS8 p.Arg434Cys Uncertain significance ★★ ⚠ same type

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-val224ile (accessed [today's date]).

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