Is EPS8L3 p.Pro466Ser (c.1396C>T) pathogenic?

EPS8L3 p.Pro466Ser (c.1396C>T) is classified Uncertain significance in EPS8L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0912); Very rare (popmax 0.00017%, nfe).

How common is EPS8L3 p.Pro466Ser (c.1396C>T) in the general population?

EPS8L3 p.Pro466Ser (c.1396C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about EPS8L3 p.Pro466Ser (c.1396C>T)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

EPS8L3 p.Pro466Ser

c.1396C>T · VCV4250304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR 0.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.48	GERP -1.2, phastCons 0.89
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.6 · regional, not allelic
Overall
CADD	5.049	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,614 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,176 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: EPS8L3
Protein: p.Pro466Ser
Coding: c.1396C>T
MANE Select: NM_133181
Type: single nucleotide variant
Location: chr1:109752033 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.46 · 1 PDB
Residue 466: a β-strand; the sh3 domain

Full EPS8L3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8L3 p.Leu453Pro Uncertain significance ★★ ⚠ same type
EPS8L3 p.Phe318Leu Uncertain significance ★★ ⚠ same type
EPS8L3 p.Thr36Ile Uncertain significance ★★ ⚠ same type
EPS8L3 p.Asp481= Benign ★★ same type
EPS8L3 p.Ala181Pro Uncertain significance ★ ⚠ same type
EPS8L3 p.Ala215Thr Uncertain significance ★ ⚠ same type
EPS8L3 p.Ala282Val Uncertain significance ★ ⚠ same type
EPS8L3 p.Ala8Thr 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/eps8l3-p-pro466ser (accessed [today's date]).

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