Is NEBL p.Ser747= (c.2241G>A) pathogenic?

NEBL p.Ser747= (c.2241G>A) is classified Uncertain significance in NEBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). Ultra-rare (popmax 0.0165%, mid); Associated with dilated cardiomyopathy.

What condition is associated with NEBL p.Ser747= (c.2241G>A)?

NEBL p.Ser747= (c.2241G>A) is associated with dilated cardiomyopathy (ClinVar).

How common is NEBL p.Ser747= (c.2241G>A) in the general population?

NEBL p.Ser747= (c.2241G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

NEBL p.Ser747=

c.2241G>A · rs377702958 · VCV1437610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.70	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.72	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.00169% 27/1,601,018 alleles · ultra-rare exomes 24/1,449,008 · genomes 3/152,010 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
East Asian	0.0156%	6,393
Remaining individualsnot grpmax-eligible	0.00161%	62,086
European (non-Finnish)	0.00145%	68,737
African / African-American	0.00134%	74,558

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.Ser747=
Coding: c.2241G>A
MANE Select: NM_006393
dbSNP: rs377702958
Type: single nucleotide variant
Location: chr10:20815625 (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.Ser747Leu Likely benign ★ 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
NEBL p.Ala264Val 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-ser747 (accessed [today's date]).

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