Is EMD p.Arg152Cys (c.454C>T) pathogenic?

EMD p.Arg152Cys (c.454C>T) is classified Conflicting classifications of pathogenicity in EMD (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.11); Ultra-rare (popmax 0.0229%, mid); Associated with Emery-Dreifuss muscular dystrophy 1, X-linked.

What condition is associated with EMD p.Arg152Cys (c.454C>T)?

EMD p.Arg152Cys (c.454C>T) is associated with Emery-Dreifuss muscular dystrophy 1, X-linked, X-linked Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Arg152Cys (c.454C>T) in the general population?

EMD p.Arg152Cys (c.454C>T) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about EMD p.Arg152Cys (c.454C>T)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

EMD p.Arg152Cys

c.454C>T · rs376456050 · VCV198043

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy 1, X-linked

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.006	GERP 0.53
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	17.51	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 · 1/4,374 alleles

Filtering AF 0.00337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00261%

Overall 0.0038% 46/1,210,546 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,374
African / African-American	0.00871%	11,476
East Asian	0.00592%	16,882
European (non-Finnish)	0.00402%	24,868
Admixed American	0.00217%	45,981
Remaining individualsnot grpmax-eligible	0.0021%	47,612

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.Arg152Cys
Coding: c.454C>T
MANE Select: NM_000117
dbSNP: rs376456050
Type: single nucleotide variant
Location: chrX:154380886 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 152: the 'interaction with f-actin' region

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

Similar variants

EMD p.Arg152His Uncertain significance ★★ ⚠ same residue
EMD p.Arg152= Likely benign ★ 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-arg152cys (accessed [today's date]).

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