Is NBEAL2 p.Pro451= (c.1353G>A) pathogenic?

NBEAL2 p.Pro451= (c.1353G>A) is classified Benign/Likely benign in NBEAL2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-31). Common (popmax 18%, amr) — too common for a highly-penetrant pathogenic allele; Associated with gray platelet syndrome.

What condition is associated with NBEAL2 p.Pro451= (c.1353G>A)?

NBEAL2 p.Pro451= (c.1353G>A) is associated with gray platelet syndrome (ClinVar).

How is Gray platelet syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NBEAL2 p.Pro451=

Q: How common is NBEAL2 p.Pro451= (c.1353G>A) in the general population?

NBEAL2 p.Pro451= (c.1353G>A) is common (popmax 18%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1353G>A · rs115611407 · VCV260578

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 18%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

gray platelet syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -14	GERP -3.2
Overall
CADD	0.125	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18% Admixed American · 9,786/54,420 alleles

Filtering AF 17.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.6%

Overall 2.76% 43,181/1,567,158 alleles · common exomes 38,427/1,414,814 · genomes 4,754/152,344 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	18%	6
East Asian	14.1%	7
Ashkenazi Jewishnot grpmax-eligible	6.18%	16
South Asian	4.23%	24
Middle Eastern	4.2%	24
Remaining individualsnot grpmax-eligible	2.99%	33
Finnishnot grpmax-eligible	1.75%	57
European (non-Finnish)	1.58%	63
African / African-American	0.974%	103
Amishnot grpmax-eligible	0.22%	455

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: NBEAL2
Protein: p.Pro451=
Coding: c.1353G>A
MANE Select: NM_015175
dbSNP: rs115611407
Type: single nucleotide variant
Location: chr3:46995088 (GRCh38)
Gene constraint: LOEUF 0.641 · pLI <0.01 (gnomAD)

Full NBEAL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

gray platelet syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Gray platelet syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

NBEAL2 p.Pro451Ala Conflicting classifications of pathogenicity ★ same residue
NBEAL2 c.4485-1G>A Pathogenic/Likely pathogenic ★★ same condition
NBEAL2 c.4485-1G>T Pathogenic/Likely pathogenic ★★ same condition
NBEAL2 p.Arg2120Gln Likely pathogenic ★★ same condition
NBEAL2 p.Arg597Ter Pathogenic ★★ same condition
NBEAL2 p.Glu1361Ter Pathogenic ★★ same condition
NBEAL2 c.2557-5C>G Uncertain significance ★★ same condition
NBEAL2 c.5459+8G>A 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/nbeal2-p-pro451 (accessed [today's date]).

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