Is NOS3 p.Glu321= (c.963G>A) pathogenic?

NOS3 p.Glu321= (c.963G>A) is classified Likely benign in NOS3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-09). Very rare (popmax 0.00017%, nfe); Associated with NOS3-related disorder.

What condition is associated with NOS3 p.Glu321= (c.963G>A)?

NOS3 p.Glu321= (c.963G>A) is associated with NOS3-related disorder (ClinVar).

How common is NOS3 p.Glu321= (c.963G>A) in the general population?

NOS3 p.Glu321= (c.963G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

NOS3 p.Glu321=

c.963G>A · rs756737838 · VCV3046811

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

NOS3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.75, phastCons 1
Overall
CADD	14.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,462 alleles

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

Overall 0.000124% 2/1,609,030 alleles · very rare exomes 2/1,456,682 · genomes 0/152,348 · joint denominator

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: NOS3
Protein: p.Glu321=
Coding: c.963G>A
MANE Select: NM_000603
dbSNP: rs756737838
Type: single nucleotide variant
Location: chr7:150999196 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20 · 105 PDB
Residue 321: an α-helix; the 'interaction with nosip' region

Full NOS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NOS3-related disorder

Similar variants

NOS3 p.Arg98Cys Uncertain significance ★ ⚠ same condition
NOS3 p.Pro795Leu Uncertain significance ⚠ same condition
NOS3 p.Gln982Leu Likely benign same condition
NOS3 p.Gly259= Likely benign same condition
NOS3 p.Leu328= Likely benign same condition
NOS3 p.Arg107Trp Uncertain significance ★★ ⚠ same type
NOS3 p.Val185Ala Uncertain significance ★★ ⚠ same type
NOS3 c.1132-253C>A Benign ★★ 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/nos3-p-glu321 (accessed [today's date]).

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