Is EPS8 p.Phe332Leu (c.996C>G) pathogenic?

EPS8 p.Phe332Leu (c.996C>G) is classified Uncertain significance in EPS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-06). AlphaMissense: ambiguous (0.4754); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EPS8 p.Phe332Leu (c.996C>G)?

EPS8 p.Phe332Leu (c.996C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPS8 p.Phe332Leu (c.996C>G) in the general population?

EPS8 p.Phe332Leu (c.996C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about EPS8 p.Phe332Leu (c.996C>G)?

AlphaMissense predicts ambiguous (score 0.4754) — an in-silico prediction, not a clinical call.

EPS8 p.Phe332Leu

c.996C>G · VCV3276103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4754	ambiguous
REVEL	0.098	moderately benign-leaning
SaProt	LLR -7.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.64	GERP -3.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	7.838	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 8.48e-05% European (non-Finnish) · 1/1,178,940 alleles

Overall 6.85e-05% 1/1,460,468 alleles · very rare

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.Phe332Leu
Coding: c.996C>G
MANE Select: NM_004447
Type: single nucleotide variant
Location: chr12:15658527 (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.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
EPS8 p.Arg597Ser 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-phe332leu (accessed [today's date]).

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