Is NBEA p.Ala75Ser (c.223G>T) pathogenic?

NBEA p.Ala75Ser (c.223G>T) is classified Uncertain significance in NBEA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-27). AlphaMissense: likely benign (0.2902); Very rare (popmax 0.00017%, nfe).

How common is NBEA p.Ala75Ser (c.223G>T) in the general population?

NBEA p.Ala75Ser (c.223G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about NBEA p.Ala75Ser (c.223G>T)?

AlphaMissense predicts likely benign (score 0.2902) — an in-silico prediction, not a clinical call.

NBEA p.Ala75Ser

c.223G>T · VCV4919714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2902	likely benign
REVEL	0.213	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 107 kb · p 5.9e-10 · regional, not allelic
Overall
CADD	33.0	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 0.00017% European (non-Finnish) · 2/1,179,618 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,264 alleles · very rare exomes 3/1,461,094 · genomes 0/152,170 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)grpmax	0.00017%	589,810

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala75Ser
Coding: c.223G>T
MANE Select: NM_001385012
Type: single nucleotide variant
Location: chr13:34943043 (GRCh38)
Gene constraint: LOEUF 0.137 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Similar variants

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NBEA p.Arg2213Ter Pathogenic/Likely pathogenic ★★ same type
NBEA p.Arg2866Ter Pathogenic ★★ same type
NBEA p.Arg696Ter Pathogenic/Likely pathogenic ★★ same type
NBEA p.Asp319Tyr Likely pathogenic ★★ same type
NBEA c.4242+5G>A Uncertain significance ★★ same type
NBEA p.Ala603Val Uncertain significance ★★ same type

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-ala75ser (accessed [today's date]).

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