Is EED p.Val139Leu (c.415G>C) pathogenic?

EED p.Val139Leu (c.415G>C) is classified Uncertain significance in EED (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.5079); Very rare (popmax 0.00382%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EED p.Val139Leu (c.415G>C)?

EED p.Val139Leu (c.415G>C) is associated with Inborn genetic diseases (ClinVar).

How common is EED p.Val139Leu (c.415G>C) in the general population?

EED p.Val139Leu (c.415G>C) is very rare (popmax 0.00382%, nfe) (gnomAD).

What do computational predictors say about EED p.Val139Leu (c.415G>C)?

AlphaMissense predicts ambiguous (score 0.5079) — an in-silico prediction, not a clinical call.

EED p.Val139Leu

c.415G>C · VCV3843456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00382%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5079	ambiguous
REVEL	0.2	benign-leaning
SaProt	LLR -8.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 28 kb · p 8.5e-32 · regional, not allelic
Overall
CADD	24.6	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 0.00382% European (non-Finnish) · 45/1,176,476 alleles

Filtering AF 0.00292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.0036% 58/1,609,074 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0209%	4,783
European (non-Finnish)grpmax	0.00382%	26,144

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EED
Protein: p.Val139Leu
Coding: c.415G>C
MANE Select: NM_003797
Type: single nucleotide variant
Location: chr11:86255276 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.21 · 81 PDB
Residue 139: the 'interaction with ezh2' region; a β-strand

Full EED 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

EED c.268-3T>C Conflicting classifications of pathogenicity ★ same condition
EED p.Ala327Ser Uncertain significance ★ ⚠ same condition
EED p.Ala41Thr Uncertain significance ★ ⚠ same condition
EED p.Arg4Ser Uncertain significance ★ ⚠ same condition
EED p.Asn102Asp Uncertain significance ★ ⚠ same condition
EED p.Asn266Thr Uncertain significance ★ ⚠ same condition
EED p.Asn272Ser Uncertain significance ★ ⚠ same condition
EED p.Asn38Thr 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/eed-p-val139leu (accessed [today's date]).

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