Is NEBL p.Ala592= (c.1776G>A) pathogenic?

NEBL p.Ala592= (c.1776G>A) is classified Uncertain significance in NEBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-27). Ultra-rare (popmax 0.0167%, mid); Associated with dilated cardiomyopathy.

What condition is associated with NEBL p.Ala592= (c.1776G>A)?

NEBL p.Ala592= (c.1776G>A) is associated with dilated cardiomyopathy (ClinVar).

How common is NEBL p.Ala592= (c.1776G>A) in the general population?

NEBL p.Ala592= (c.1776G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

NEBL p.Ala592=

c.1776G>A · rs113406843 · VCV489174

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP -5	GERP -4.9
Overall
CADD	2.052	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,978 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.0016% 25/1,564,008 alleles · ultra-rare exomes 22/1,411,820 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,978
African / African-American	0.00949%	10,541
Admixed American	0.00167%	59,792
Remaining individualsnot grpmax-eligible	0.00164%	60,834
European (non-Finnish)	0.00132%	75,666

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: NEBL
Protein: p.Ala592=
Coding: c.1776G>A
MANE Select: NM_006393
dbSNP: rs113406843
Type: single nucleotide variant
Location: chr10:20828530 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 62.00 · 1 PDB

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

Disease context

dilated cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NEBL p.Ala592Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
NEBL p.Ala592Val Conflicting classifications of pathogenicity ★ ⚠ same residue
NEBL c.1227+5G>A Uncertain significance ★★ same condition
NEBL c.1870-1G>A Uncertain significance ★★ same condition
NEBL c.798+1G>A Uncertain significance ★★ same condition
NEBL c.903+1G>T Uncertain significance ★★ same condition
NEBL p.Ala114Ser Uncertain significance ★★ ⚠ same condition
NEBL p.Ala219Thr Uncertain significance ★★ ⚠ 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/nebl-p-ala592 (accessed [today's date]).

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