Is EMD p.Val26Ala (c.77T>C) pathogenic?

EMD p.Val26Ala (c.77T>C) is classified Conflicting classifications of pathogenicity in EMD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.8146); Very rare (popmax 0.000114%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EMD p.Val26Ala (c.77T>C)?

EMD p.Val26Ala (c.77T>C) is associated with Cardiovascular phenotype, X-linked Emery-Dreifuss muscular dystrophy, Emery-Dreifuss muscular dystrophy (ClinVar).

How common is EMD p.Val26Ala (c.77T>C) in the general population?

EMD p.Val26Ala (c.77T>C) is very rare (popmax 0.000114%, nfe) (gnomAD).

What do computational predictors say about EMD p.Val26Ala (c.77T>C)?

AlphaMissense predicts likely pathogenic (score 0.8146) — an in-silico prediction, not a clinical call.

EMD p.Val26Ala

c.77T>C · rs727505029 · VCV179659

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8146 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000114%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8146	likely pathogenic · top 6% in EMD
REVEL	0.245	benign-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,709 bp · p 0.47 · regional, not allelic
Overall
CADD	23.7	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 0.000114% European (non-Finnish) · 1/874,030 alleles

Overall 0.000189% 2/1,056,063 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00217%	46,001
European (non-Finnish)grpmax	0.000114%	874,027

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val26Ala
Coding: c.77T>C
MANE Select: NM_000117
dbSNP: rs727505029
Type: single nucleotide variant
Location: chrX:154379561 (GRCh38)
Structure: AlphaFold pLDDT 61.26 · 6 PDB
Residue 26: the lem domain

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 Emery-Dreifuss muscular dystrophy 1, X-linked

Similar variants

EMD p.Val26_Val27insTer 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-val26ala (accessed [today's date]).

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