Is NEBL p.Ala477Pro (c.1429G>C) pathogenic?

NEBL p.Ala477Pro (c.1429G>C) is classified Uncertain significance in NEBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely pathogenic (0.9732); Ultra-rare (popmax 0.02%, eas); Associated with dilated cardiomyopathy.

What condition is associated with NEBL p.Ala477Pro (c.1429G>C)?

NEBL p.Ala477Pro (c.1429G>C) is associated with dilated cardiomyopathy (ClinVar).

How common is NEBL p.Ala477Pro (c.1429G>C) in the general population?

NEBL p.Ala477Pro (c.1429G>C) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about NEBL p.Ala477Pro (c.1429G>C)?

AlphaMissense predicts likely pathogenic (score 0.9732) — an in-silico prediction, not a clinical call.

NEBL p.Ala477Pro

c.1429G>C · rs758358892 · VCV1025734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9732	likely pathogenic · top 1% in NEBL
REVEL	0.369	indeterminate
SaProt	LLR -15.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 111 kb · p 7.4e-07 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.02% East Asian · 9/44,894 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00732% 118/1,611,914 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.02%	4,988
Remaining individualsnot grpmax-eligible	0.016%	6,246
European (non-Finnish)	0.00822%	12,159
Admixed American	0.00333%	29,998

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.Ala477Pro
Coding: c.1429G>C
MANE Select: NM_006393
dbSNP: rs758358892
Type: single nucleotide variant
Location: chr10:20835533 (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.Ala477Thr Uncertain significance ★ ⚠ same residue
NEBL p.Ala477_Ala478insTer Uncertain significance ★ 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-ala477pro (accessed [today's date]).

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