Is EML5 p.Asp520Tyr (c.1558G>T) pathogenic?

EML5 p.Asp520Tyr (c.1558G>T) is classified Uncertain significance in EML5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: ambiguous (0.4086); Very rare (popmax 0.00893%, eas).

How common is EML5 p.Asp520Tyr (c.1558G>T) in the general population?

EML5 p.Asp520Tyr (c.1558G>T) is very rare (popmax 0.00893%, eas) (gnomAD).

What do computational predictors say about EML5 p.Asp520Tyr (c.1558G>T)?

AlphaMissense predicts ambiguous (score 0.4086) — an in-silico prediction, not a clinical call.

EML5 p.Asp520Tyr

c.1558G>T · rs748201571 · VCV3088701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Computational evidence

Protein change
AlphaMissense	0.4086	ambiguous
REVEL	0.537	indeterminate
SaProt	LLR -9.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 113 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	25.7	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 0.00893% East Asian · 4/44,794 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,613,266 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,198
European (non-Finnish)	8.48e-05%	1,179,439

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.Asp520Tyr
Coding: c.1558G>T
MANE Select: NM_183387
dbSNP: rs748201571
Type: single nucleotide variant
Location: chr14:88712370 (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-asp520tyr (accessed [today's date]).

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