Is NBEA p.Ile554Val (c.1660A>G) pathogenic?

NBEA p.Ile554Val (c.1660A>G) is classified Uncertain significance in NBEA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely benign (0.2314); Very rare (popmax 0.000172%, nfe); Associated with neurodevelopmental disorder with or without early-onset generalized epilepsy.

What condition is associated with NBEA p.Ile554Val (c.1660A>G)?

NBEA p.Ile554Val (c.1660A>G) is associated with neurodevelopmental disorder with or without early-onset generalized epilepsy (ClinVar).

How common is NBEA p.Ile554Val (c.1660A>G) in the general population?

NBEA p.Ile554Val (c.1660A>G) is very rare (popmax 0.000172%, nfe) (gnomAD).

What do computational predictors say about NBEA p.Ile554Val (c.1660A>G)?

AlphaMissense predicts likely benign (score 0.2314) — an in-silico prediction, not a clinical call.

NBEA p.Ile554Val

c.1660A>G · VCV4079359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2314 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000172%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

neurodevelopmental disorder with or without early-onset generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.2314	likely benign
REVEL	0.284	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 86 kb · p 2.9e-12 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000172% European (non-Finnish) · 2/1,164,060 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00014% 2/1,433,222 alleles · very rare

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: NBEA
Protein: p.Ile554Val
Coding: c.1660A>G
MANE Select: NM_001385012
Type: single nucleotide variant
Location: chr13:35098385 (GRCh38)
Gene constraint: LOEUF 0.137 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 554: 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-ile554val (accessed [today's date]).

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