Is EPS8 p.Ile668= (c.2004C>T) pathogenic?

EPS8 p.Ile668= (c.2004C>T) is classified Likely benign in EPS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-10-23). Ultra-rare (popmax 0.0535%, eas).

How common is EPS8 p.Ile668= (c.2004C>T) in the general population?

EPS8 p.Ile668= (c.2004C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

EPS8 p.Ile668=

c.2004C>T · rs187750650 · VCV792837

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -5.6
Overall
CADD	4.669	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% East Asian · 24/44,880 alleles

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

Overall 0.00328% 53/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
Remaining individualsnot grpmax-eligible	0.0032%	31,252
South Asian	0.0022%	45,538
European (non-Finnish)	0.00212%	47,199

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.Ile668=
Coding: c.2004C>T
MANE Select: NM_004447
dbSNP: rs187750650
Type: single nucleotide variant
Location: chr12:15631482 (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 668: the 'disordered' region; the 'effector region' region

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

Similar variants

EPS8 p.Ile668Thr Uncertain significance ★ ⚠ same residue
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

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-ile668 (accessed [today's date]).

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