Is NOS3 p.Arg329His (c.986G>A) pathogenic?

NOS3 p.Arg329His (c.986G>A) is classified Uncertain significance in NOS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1188); Very rare (popmax 0.0022%, sas).

How common is NOS3 p.Arg329His (c.986G>A) in the general population?

NOS3 p.Arg329His (c.986G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about NOS3 p.Arg329His (c.986G>A)?

AlphaMissense predicts likely benign (score 0.1188) — an in-silico prediction, not a clinical call.

NOS3 p.Arg329His

c.986G>A · VCV4121593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1188	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.77, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,990 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000683% 11/1,610,824 alleles · very rare exomes 8/1,458,612 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,495
African / African-American	0.00134%	74,872
European (non-Finnish)	0.000678%	147,408

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.Arg329His
Coding: c.986G>A
MANE Select: NM_000603
Type: single nucleotide variant
Location: chr7:150999219 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20 · 105 PDB
Residue 329: a β-strand; the 'interaction with nosip' region

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

Similar variants

NOS3 p.Arg107Trp Uncertain significance ★★ ⚠ same type
NOS3 p.Val185Ala Uncertain significance ★★ ⚠ same type
NOS3 c.1132-253C>A Benign ★★ same type
NOS3 c.1752+1245A>G Benign ★★ same type
NOS3 c.1752+1554C>A Benign ★★ same type
NOS3 c.1752+899G>A Benign ★★ same type
NOS3 c.1821-62G>T Benign ★★ same type
NOS3 c.2112+36C>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-arg329his (accessed [today's date]).

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