Is EML1 p.Leu59Val (c.175C>G) pathogenic?

EML1 p.Leu59Val (c.175C>G) is classified Uncertain significance in EML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: ambiguous (0.5233); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with EML1 p.Leu59Val (c.175C>G)?

EML1 p.Leu59Val (c.175C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EML1 p.Leu59Val (c.175C>G) in the general population?

EML1 p.Leu59Val (c.175C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about EML1 p.Leu59Val (c.175C>G)?

AlphaMissense predicts ambiguous (score 0.5233) — an in-silico prediction, not a clinical call.

EML1 p.Leu59Val

c.175C>G · VCV4017807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5233 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5233	ambiguous
REVEL	0.186	benign-leaning
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.1, phastCons 0.96
Regional constraint	o/e 0.88	unconstrained · MANE · 101 kb · p 0.064 · regional, not allelic
Overall
CADD	24.2	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 0.0167% Admixed American · 10/60,006 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000743% 12/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,001
East Asian	0.00223%	44,898
European (non-Finnish)	8.47e-05%	1,180,043

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: EML1
Protein: p.Leu59Val
Coding: c.175C>G
MANE Select: NM_004434
Type: single nucleotide variant
Location: chr14:99850960 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.49 · 1 PDB

Full EML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EML1 p.Arg192His Uncertain significance ★★ ⚠ same condition
EML1 p.Arg450Gln Uncertain significance ★★ ⚠ same condition
EML1 p.Arg813His Uncertain significance ★★ ⚠ same condition
EML1 p.Cys369Phe Uncertain significance ★★ ⚠ same condition
EML1 p.Gln409Glu Uncertain significance ★★ ⚠ same condition
EML1 p.His351Gln Uncertain significance ★★ ⚠ same condition
EML1 p.Val253Met Uncertain significance ★★ ⚠ same condition
EML1 p.Val688Met Uncertain significance ★★ ⚠ same condition

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/eml1-p-leu59val (accessed [today's date]).

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