Is NBEA p.Leu685Pro (c.2054T>C) pathogenic?

NBEA p.Leu685Pro (c.2054T>C) is classified Uncertain significance in NBEA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-22). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with or without early-onset generalized epilepsy.

What condition is associated with NBEA p.Leu685Pro (c.2054T>C)?

NBEA p.Leu685Pro (c.2054T>C) is associated with neurodevelopmental disorder with or without early-onset generalized epilepsy (ClinVar).

How common is NBEA p.Leu685Pro (c.2054T>C) in the general population?

NBEA p.Leu685Pro (c.2054T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBEA p.Leu685Pro (c.2054T>C)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

NBEA p.Leu685Pro

c.2054T>C · VCV4871900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,380,414)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

neurodevelopmental disorder with or without early-onset generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic · top 6% in NBEA
REVEL	0.819	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 86 kb · p 2.9e-12 · regional, not allelic
Overall
CADD	27.7	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,380,414). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NBEA
Protein: p.Leu685Pro
Coding: c.2054T>C
MANE Select: NM_001385012
Type: single nucleotide variant
Location: chr13:35117465 (GRCh38)
Gene constraint: LOEUF 0.137 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 685: a UniProt-annotated variant site (in nedege)

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

Disease context

neurodevelopmental disorder with or without early-onset generalized epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NBEA p.Arg1299Ter Pathogenic/Likely pathogenic ★★ same condition
NBEA p.Arg2866Ter Pathogenic ★★ same condition
NBEA p.Arg696Ter Pathogenic/Likely pathogenic ★★ same condition
NBEA p.Ala603Val Uncertain significance ★★ same condition
NBEA p.Asn1141Asp Uncertain significance ★★ ⚠ same condition
NBEA p.Asn1599Ser Uncertain significance ★★ ⚠ same condition
NBEA p.Asp2789Asn Uncertain significance ★★ same condition
NBEA p.Asp701Glu 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/nbea-p-leu685pro (accessed [today's date]).

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