Is EMD p.Leu84Val (c.250C>G) pathogenic?

EMD p.Leu84Val (c.250C>G) is classified Uncertain significance in EMD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). AlphaMissense: likely benign (0.1609); Very rare (popmax 0.000223%, nfe); Associated with X-linked Emery-Dreifuss muscular dystrophy.

What condition is associated with EMD p.Leu84Val (c.250C>G)?

EMD p.Leu84Val (c.250C>G) is associated with X-linked Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Leu84Val (c.250C>G) in the general population?

EMD p.Leu84Val (c.250C>G) is very rare (popmax 0.000223%, nfe) (gnomAD).

How is Emery-Dreifuss muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EMD p.Leu84Val (c.250C>G)?

AlphaMissense predicts likely benign (score 0.1609) — an in-silico prediction, not a clinical call.

EMD p.Leu84Val

c.250C>G · VCV3665668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.1609	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -6.99	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 3.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	19.44	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 0.000223% European (non-Finnish) · 2/895,238 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000182% 2/1,097,734 alleles · very rare

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: EMD
Protein: p.Leu84Val
Coding: c.250C>G
MANE Select: NM_000117
Type: single nucleotide variant
Location: chrX:154380004 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 84: the 'interaction with f-actin' region

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

Disease context

X-linked Emery-Dreifuss muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Emery-Dreifuss muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

EMD p.Leu84= Likely benign ★ same residue
EMD p.Leu84fs Pathogenic ★★ same residue
EMD c.187+1G>A Pathogenic ★★ same condition
EMD c.187+1G>T Pathogenic/Likely pathogenic ★★ same condition
EMD c.265+1G>A Likely pathogenic ★★ same condition
EMD c.266-2A>G Pathogenic ★★ same condition
EMD c.266-3A>G Pathogenic ★★ same condition
EMD c.399+1G>T Pathogenic ★★ 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/emd-p-leu84val (accessed [today's date]).

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