Is NOS3 p.Pro236Ser (c.706C>T) pathogenic?

NOS3 p.Pro236Ser (c.706C>T) is classified Uncertain significance in NOS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0737); Very rare (popmax 8.48e-05%, nfe).

How common is NOS3 p.Pro236Ser (c.706C>T) in the general population?

NOS3 p.Pro236Ser (c.706C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NOS3 p.Pro236Ser (c.706C>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

NOS3 p.Pro236Ser

c.706C>T · VCV4121608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -0.99
Overall
CADD	15.82	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,812 alleles

Overall 6.86e-05% 1/1,457,136 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: NOS3
Protein: p.Pro236Ser
Coding: c.706C>T
MANE Select: NM_000603
Type: single nucleotide variant
Location: chr7:150998570 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20 · 105 PDB
Residue 236: 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-pro236ser (accessed [today's date]).

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