Is EMD p.Pro224Leu (c.671C>T) pathogenic?

EMD p.Pro224Leu (c.671C>T) is classified Conflicting classifications of pathogenicity in EMD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-02-13). AlphaMissense: ambiguous (0.5034); Ultra-rare (popmax 0.0229%, mid); Associated with Emery-Dreifuss muscular dystrophy 1, X-linked.

What condition is associated with EMD p.Pro224Leu (c.671C>T)?

EMD p.Pro224Leu (c.671C>T) is associated with Emery-Dreifuss muscular dystrophy 1, X-linked, X-linked Emery-Dreifuss muscular dystrophy, Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Pro224Leu (c.671C>T) in the general population?

EMD p.Pro224Leu (c.671C>T) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about EMD p.Pro224Leu (c.671C>T)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

EMD p.Pro224Leu

c.671C>T · rs782559230 · VCV201777

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Emery-Dreifuss muscular dystrophy 1, X-linked

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.692	pathogenic-leaning
SaProt	LLR -9.77	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	23.6	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 0.0229% Middle Eastern · 1/4,373 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00235%

Overall 0.00124% 15/1,210,608 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,373
East Asian	0.0118%	8,451
European (non-Finnish)	0.00112%	89,519

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.Pro224Leu
Coding: c.671C>T
MANE Select: NM_000117
dbSNP: rs782559230
Type: single nucleotide variant
Location: chrX:154381103 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB

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

Disease context

Emery-Dreifuss muscular dystrophy 1, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy

Similar variants

EMD p.Pro224Arg Uncertain significance ★★ ⚠ same residue
EMD p.Pro224= Likely benign ★★ same residue
EMD p.Pro224Ser Uncertain significance ★ ⚠ 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

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-pro224leu (accessed [today's date]).

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