Is EPS8L2 p.Arg453Pro (c.1358G>C) pathogenic?

EPS8L2 p.Arg453Pro (c.1358G>C) is classified Uncertain significance in EPS8L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1431); Very rare (popmax 0.00111%, sas).

How common is EPS8L2 p.Arg453Pro (c.1358G>C) in the general population?

EPS8L2 p.Arg453Pro (c.1358G>C) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about EPS8L2 p.Arg453Pro (c.1358G>C)?

AlphaMissense predicts likely benign (score 0.1431) — an in-silico prediction, not a clinical call.

EPS8L2 p.Arg453Pro

c.1358G>C · rs371425662 · VCV2492040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1431	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.57	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 5.6	GERP -0.19, phastCons 0.99
Regional constraint	o/e 1.19	unconstrained · MANE · 18 kb · p 2.2e-09 · regional, not allelic
Overall
CADD	19.12	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 0.00111% South Asian · 1/89,832 alleles

Overall 0.000138% 2/1,452,898 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,832
European (non-Finnish)	8.5e-05%	1,176,338

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: EPS8L2
Protein: p.Arg453Pro
Coding: c.1358G>C
MANE Select: NM_022772
dbSNP: rs371425662
Type: single nucleotide variant
Location: chr11:723257 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 2 PDB
Residue 453: the 'disordered' region

Full EPS8L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8L2 p.Arg453Gln Uncertain significance ★ ⚠ same residue
EPS8L2 p.Glu165Ter Likely pathogenic ★★ same type
EPS8L2 p.Arg102Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg193Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg245Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg272Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg365Cys Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg506Leu 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/eps8l2-p-arg453pro (accessed [today's date]).

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