Is EML6 p.Pro496Ala (c.1486C>G) pathogenic?

EML6 p.Pro496Ala (c.1486C>G) is classified Uncertain significance in EML6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely benign (0.0628); Very rare (popmax 0.00489%, eas).

How common is EML6 p.Pro496Ala (c.1486C>G) in the general population?

EML6 p.Pro496Ala (c.1486C>G) is very rare (popmax 0.00489%, eas) (gnomAD).

What do computational predictors say about EML6 p.Pro496Ala (c.1486C>G)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

EML6 p.Pro496Ala

c.1486C>G · VCV3275379

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00489%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -5.27	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 2.2	GERP 1.7, phastCons 0.067
Regional constraint	o/e 1.20	unconstrained · MANE · 245 kb · p 7.8e-23 · regional, not allelic
Overall
CADD	20.8	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 0.00489% East Asian · 2/40,864 alleles

Filtering AF 0.000811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000303%

Overall 0.000286% 4/1,397,524 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00489%	20,432
Remaining individualsnot grpmax-eligible	0.00167%	60,036
South Asian	0.00119%	83,702

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: EML6
Protein: p.Pro496Ala
Coding: c.1486C>G
MANE Select: NM_001039753
Type: single nucleotide variant
Location: chr2:54853684 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.42

Full EML6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML6 p.Pro496Leu Uncertain significance ★ ⚠ same residue
EML6 p.Arg475Gln Uncertain significance ★★ ⚠ same type
EML6 p.Gly1925Ser Uncertain significance ★★ ⚠ same type
EML6 p.Thr199Ser Uncertain significance ★★ ⚠ same type
EML6 p.Glu1412= Benign ★★ same type
EML6 p.His1237= Benign ★★ same type
EML6 p.His662= Benign ★★ same type
EML6 p.Ile220= Benign ★★ 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/eml6-p-pro496ala (accessed [today's date]).

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