Is EPS8L3 p.Arg485Trp (c.1453C>T) pathogenic?

EPS8L3 p.Arg485Trp (c.1453C>T) is classified Uncertain significance in EPS8L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.2786); Ultra-rare (popmax 0.0166%, mid).

How common is EPS8L3 p.Arg485Trp (c.1453C>T) in the general population?

EPS8L3 p.Arg485Trp (c.1453C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about EPS8L3 p.Arg485Trp (c.1453C>T)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

EPS8L3 p.Arg485Trp

c.1453C>T · VCV4664982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -14.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 3.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.6 · regional, not allelic
Overall
CADD	31.0	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 0.0166% Middle Eastern · 1/6,032 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00273% 44/1,613,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,032
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.00322%	31,052
South Asian	0.0022%	45,538

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.Arg485Trp
Coding: c.1453C>T
MANE Select: NM_133181
Type: single nucleotide variant
Location: chr1:109751764 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.46 · 1 PDB
Residue 485: the sh3 domain; a β-strand

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-arg485trp (accessed [today's date]).

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