Is EPS8 p.Ile700Thr (c.2099T>C) pathogenic?

EPS8 p.Ile700Thr (c.2099T>C) is classified Benign/Likely benign in EPS8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.4652); Rare (popmax 0.277%, nfe).

How common is EPS8 p.Ile700Thr (c.2099T>C) in the general population?

EPS8 p.Ile700Thr (c.2099T>C) is rare (popmax 0.277%, nfe) (gnomAD).

What do computational predictors say about EPS8 p.Ile700Thr (c.2099T>C)?

AlphaMissense predicts ambiguous (score 0.4652) — an in-silico prediction, not a clinical call.

EPS8 p.Ile700Thr

c.2099T>C · rs111934716 · VCV667046

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4652 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.277%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4652	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -7.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	22.0	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 0.277% European (non-Finnish) · 3,257/1,175,056 alleles

Filtering AF 0.269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.266%

Overall 0.25% 4,011/1,606,914 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.913%	110
European (non-Finnish)grpmax	0.277%	361
Remaining individualsnot grpmax-eligible	0.196%	510
African / African-American	0.04%	2,498
Admixed American	0.0285%	3,514
South Asian	0.00222%	45,092

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.Ile700Thr
Coding: c.2099T>C
MANE Select: NM_004447
dbSNP: rs111934716
Type: single nucleotide variant
Location: chr12:15624353 (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 700: the 'effector region' 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-ile700thr (accessed [today's date]).

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