Is NEBL p.Pro214Ser (c.640C>T) pathogenic?

NEBL p.Pro214Ser (c.640C>T) is classified Uncertain significance in NEBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-20). AlphaMissense: ambiguous (0.3662); Absent from gnomAD v4.1; Associated with dilated cardiomyopathy.

What condition is associated with NEBL p.Pro214Ser (c.640C>T)?

NEBL p.Pro214Ser (c.640C>T) is associated with dilated cardiomyopathy (ClinVar).

How common is NEBL p.Pro214Ser (c.640C>T) in the general population?

NEBL p.Pro214Ser (c.640C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEBL p.Pro214Ser (c.640C>T)?

AlphaMissense predicts ambiguous (score 0.3662) — an in-silico prediction, not a clinical call.

NEBL p.Pro214Ser

c.640C>T · VCV4690713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3662 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3662	ambiguous
REVEL	0.21	benign-leaning
SaProt	LLR -7.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 111 kb · p 7.4e-07 · regional, not allelic
Overall
CADD	21.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEBL
Protein: p.Pro214Ser
Coding: c.640C>T
MANE Select: NM_006393
Type: single nucleotide variant
Location: chr10:20868708 (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.Pro214Ala Uncertain significance ★ ⚠ same residue
NEBL p.Pro214Leu Uncertain significance ★ ⚠ same residue
NEBL p.Pro214Thr 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

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-pro214ser (accessed [today's date]).

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