Is EMD p.Ser54Cys (c.161C>G) pathogenic?

EMD p.Ser54Cys (c.161C>G) is classified Uncertain significance in EMD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). AlphaMissense: likely benign (0.1751); Very rare (popmax 0.00664%, amr); Associated with X-linked Emery-Dreifuss muscular dystrophy.

What condition is associated with EMD p.Ser54Cys (c.161C>G)?

EMD p.Ser54Cys (c.161C>G) is associated with X-linked Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Ser54Cys (c.161C>G) in the general population?

EMD p.Ser54Cys (c.161C>G) is very rare (popmax 0.00664%, amr) (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.Ser54Cys (c.161C>G)?

AlphaMissense predicts likely benign (score 0.1751) — an in-silico prediction, not a clinical call.

EMD p.Ser54Cys

c.161C>G · VCV4751371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00664%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

X-linked Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.1751	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	21.4	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 0.00664% Admixed American · 3/45,174 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000888%

Overall 0.000249% 3/1,203,904 alleles · very rare exomes 2/1,092,198 · genomes 1/111,706 · joint denominator

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.Ser54Cys
Coding: c.161C>G
MANE Select: NM_000117
Type: single nucleotide variant
Location: chrX:154379768 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 54: a UniProt-annotated variant site (in edmd1; likely pathogenic; unable to rescue impaired differentiation of emd-deficient myogenic progenitor cells; no loss of binding to f-actin; enhanced rate of actin polymerization and loss of binding to bclaf1); the 'interaction with f-actin' region; a modified residue (phosphoserine)

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.Ser54= Likely benign ★ same residue
EMD p.Ser54Phe Conflicting classifications of pathogenicity ★ ⚠ 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-ser54cys (accessed [today's date]).

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