Is EMD p.Trp226Ser (c.677G>C) pathogenic?

EMD p.Trp226Ser (c.677G>C) is classified Conflicting classifications of pathogenicity in EMD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.7192); Very rare (popmax 0.00523%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Trp226Ser (c.677G>C)?

EMD p.Trp226Ser (c.677G>C) is associated with Cardiovascular phenotype, X-linked Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Trp226Ser (c.677G>C) in the general population?

EMD p.Trp226Ser (c.677G>C) is very rare (popmax 0.00523%, afr) (gnomAD).

What do computational predictors say about EMD p.Trp226Ser (c.677G>C)?

AlphaMissense predicts likely pathogenic (score 0.7192) — an in-silico prediction, not a clinical call.

EMD p.Trp226Ser

c.677G>C · rs141732118 · VCV1385301

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00523%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7192	likely pathogenic · top 10% in EMD
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -10.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	25.5	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 0.00523% African / African-American · 3/57,372 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00363% 44/1,210,486 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00523%	19,124
European (non-Finnish)	0.00436%	22,953
Remaining individualsnot grpmax-eligible	0.0042%	23,804

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.Trp226Ser
Coding: c.677G>C
MANE Select: NM_000117
dbSNP: rs141732118
Type: single nucleotide variant
Location: chrX:154381109 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB

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

Similar variants

EMD p.Trp226fs 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
EMD c.399+2T>C 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-trp226ser (accessed [today's date]).

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