Is EPS8L3 p.Arg495Trp (c.1483C>T) pathogenic?

EPS8L3 p.Arg495Trp (c.1483C>T) is classified Uncertain significance in EPS8L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely benign (0.1223); Rare (popmax 0.132%, nfe).

How common is EPS8L3 p.Arg495Trp (c.1483C>T) in the general population?

EPS8L3 p.Arg495Trp (c.1483C>T) is rare (popmax 0.132%, nfe) (gnomAD).

What do computational predictors say about EPS8L3 p.Arg495Trp (c.1483C>T)?

AlphaMissense predicts likely benign (score 0.1223) — an in-silico prediction, not a clinical call.

EPS8L3 p.Arg495Trp

c.1483C>T · VCV4664980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1223 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1223	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -10.76	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 3.1	GERP 1.3, phastCons 0.37
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.6 · regional, not allelic
Overall
CADD	21.0	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 0.132% European (non-Finnish) · 1,554/1,179,978 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.107% 1,732/1,613,710 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.159%	630
European (non-Finnish)grpmax	0.132%	759
Remaining individualsnot grpmax-eligible	0.0784%	1,276
Admixed American	0.0583%	1,714
Finnishnot grpmax-eligible	0.047%	2,127
South Asian	0.011%	9,108
African / African-American	0.00934%	10,709

Ashkenazi Jewish 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: EPS8L3
Protein: p.Arg495Trp
Coding: c.1483C>T
MANE Select: NM_133181
Type: single nucleotide variant
Location: chr1:109751734 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.46 · 1 PDB
Residue 495: 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-arg495trp (accessed [today's date]).

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