Is EML5 p.Val566Ile (c.1696G>A) pathogenic?

EML5 p.Val566Ile (c.1696G>A) is classified Uncertain significance in EML5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.0786); Ultra-rare (popmax 0.0165%, mid).

How common is EML5 p.Val566Ile (c.1696G>A) in the general population?

EML5 p.Val566Ile (c.1696G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EML5 p.Val566Ile (c.1696G>A)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

EML5 p.Val566Ile

c.1696G>A · VCV3508330

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -8.49	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 0.84	GERP -0.012, phastCons 0.27
Regional constraint	o/e 0.86	unconstrained · MANE · 113 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	17.87	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 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00175% 28/1,603,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
Admixed American	0.012%	8,366
African / African-American	0.00402%	24,859
East Asian	0.00225%	44,516
Remaining individualsnot grpmax-eligible	0.00161%	62,024
European (non-Finnish)	0.00128%	78,385

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: EML5
Protein: p.Val566Ile
Coding: c.1696G>A
MANE Select: NM_183387
Type: single nucleotide variant
Location: chr14:88706388 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.18

Full EML5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EML5 p.Ala1787Glu Benign ★★ same type
EML5 p.Thr194Met Benign ★★ same type
EML5 p.Val1361= Benign ★★ same type
EML5 p.Ala1575Thr Uncertain significance ★ ⚠ same type
EML5 p.Ala1606Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1615Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1746Val Uncertain significance ★ ⚠ same type
EML5 p.Ala1787Ser 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/eml5-p-val566ile (accessed [today's date]).

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