Is EMD p.Ala56Thr (c.166G>A) pathogenic?

EMD p.Ala56Thr (c.166G>A) is classified Conflicting classifications of pathogenicity in EMD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0778); Very rare (popmax 0.00325%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Ala56Thr (c.166G>A)?

EMD p.Ala56Thr (c.166G>A) is associated with Cardiovascular phenotype, X-linked Emery-Dreifuss muscular dystrophy, Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Ala56Thr (c.166G>A) in the general population?

EMD p.Ala56Thr (c.166G>A) is very rare (popmax 0.00325%, nfe) (gnomAD).

What do computational predictors say about EMD p.Ala56Thr (c.166G>A)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

EMD p.Ala56Thr

c.166G>A · rs1057520579 · VCV379342

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00325%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2.2
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	10.96	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 0.00325% European (non-Finnish) · 29/892,315 alleles

Filtering AF 0.00228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00197%

Overall 0.00284% 31/1,091,477 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00325%	30,770
Remaining individualsnot grpmax-eligible	0.00211%	47,363
African / African-American	0.00174%	57,533

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.Ala56Thr
Coding: c.166G>A
MANE Select: NM_000117
dbSNP: rs1057520579
Type: single nucleotide variant
Location: chrX:154379773 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 56: the 'interaction with f-actin' 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.Ala56= Conflicting classifications of pathogenicity ★ same residue
EMD p.Ala56Val 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
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-ala56thr (accessed [today's date]).

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