Is EML3 p.Pro469Leu (c.1406C>T) pathogenic?

EML3 p.Pro469Leu (c.1406C>T) is classified Uncertain significance in EML3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.1139); Ultra-rare (popmax 0.011%, sas).

How common is EML3 p.Pro469Leu (c.1406C>T) in the general population?

EML3 p.Pro469Leu (c.1406C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about EML3 p.Pro469Leu (c.1406C>T)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

EML3 p.Pro469Leu

c.1406C>T · rs143273389 · VCV2410601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.93, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,978 bp · p 8e-12 · 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 0.011% South Asian · 10/91,086 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.0044% 71/1,613,978 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,109
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00458%	21,852
African / African-American	0.00401%	24,968

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.Pro469Leu
Coding: c.1406C>T
MANE Select: NM_153265
dbSNP: rs143273389
Type: single nucleotide variant
Location: chr11:62607056 (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-pro469leu (accessed [today's date]).

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