Is EMD p.Arg168Cys (c.502C>T) pathogenic?

EMD p.Arg168Cys (c.502C>T) is classified Uncertain significance in EMD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-27). AlphaMissense: likely benign (0.1923); Ultra-rare (popmax 0.0193%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Arg168Cys (c.502C>T)?

EMD p.Arg168Cys (c.502C>T) is associated with Cardiovascular phenotype, X-linked Emery-Dreifuss muscular dystrophy, Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Arg168Cys (c.502C>T) in the general population?

EMD p.Arg168Cys (c.502C>T) is ultra-rare (popmax 0.0193%, sas) (gnomAD).

What do computational predictors say about EMD p.Arg168Cys (c.502C>T)?

AlphaMissense predicts likely benign (score 0.1923) — an in-silico prediction, not a clinical call.

EMD p.Arg168Cys

c.502C>T · rs886044839 · VCV285132

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0193%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1923	likely benign
REVEL	0.663	pathogenic-leaning
SaProt	LLR -11.48	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	25.1	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 0.0193% South Asian · 11/57,012 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00833%

Overall 0.00146% 16/1,097,977 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0193%	5,183
East Asian	0.00296%	33,839
Remaining individualsnot grpmax-eligible	0.0021%	47,646
European (non-Finnish)	0.000335%	298,489

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.Arg168Cys
Coding: c.502C>T
MANE Select: NM_000117
dbSNP: rs886044839
Type: single nucleotide variant
Location: chrX:154380934 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 168: the 'interaction with f-actin' region; the 'interaction with ctnnb1' region

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

Disease context

Cardiovascular phenotype — 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.Arg168His Uncertain significance ★ ⚠ same residue
EMD p.Arg168Leu Uncertain significance ★ ⚠ same residue
EMD p.Arg168= 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

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-arg168cys (accessed [today's date]).

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