Is EML3 p.Arg582Ser (c.1746G>C) pathogenic?

EML3 p.Arg582Ser (c.1746G>C) is classified Uncertain significance in EML3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: ambiguous (0.5072); Very rare (popmax 0.0022%, sas).

How common is EML3 p.Arg582Ser (c.1746G>C) in the general population?

EML3 p.Arg582Ser (c.1746G>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EML3 p.Arg582Ser (c.1746G>C)?

AlphaMissense predicts ambiguous (score 0.5072) — an in-silico prediction, not a clinical call.

EML3 p.Arg582Ser

c.1746G>C · VCV4017822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5072	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -9.03	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 0.41	GERP -2.8, phastCons 0.99
Regional constraint	o/e 0.77	unconstrained · MANE · 6,978 bp · p 8e-12 · regional, not allelic
Overall
CADD	20.7	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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000137% 2/1,461,872 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: EML3
Protein: p.Arg582Ser
Coding: c.1746G>C
MANE Select: NM_153265
Type: single nucleotide variant
Location: chr11:62605891 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.62

Full EML3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML3 p.Ala178Ser Uncertain significance ★ ⚠ same type
EML3 p.Ala366Val Uncertain significance ★ ⚠ same type
EML3 p.Ala38Val Uncertain significance ★ ⚠ same type
EML3 p.Ala512Ser Uncertain significance ★ ⚠ same type
EML3 p.Ala875Thr Uncertain significance ★ ⚠ same type
EML3 p.Arg141Gly Uncertain significance ★ ⚠ same type
EML3 p.Arg165Gln Uncertain significance ★ ⚠ same type
EML3 p.Arg165Trp 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/eml3-p-arg582ser (accessed [today's date]).

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