Is NOS3 p.Pro232Leu (c.695C>T) pathogenic?

NOS3 p.Pro232Leu (c.695C>T) is classified Uncertain significance in NOS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.7432); Very rare (popmax 0.00503%, amr).

How common is NOS3 p.Pro232Leu (c.695C>T) in the general population?

NOS3 p.Pro232Leu (c.695C>T) is very rare (popmax 0.00503%, amr) (gnomAD).

What do computational predictors say about NOS3 p.Pro232Leu (c.695C>T)?

AlphaMissense predicts likely pathogenic (score 0.7432) — an in-silico prediction, not a clinical call.

NOS3 p.Pro232Leu

c.695C>T · VCV3406787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7432	likely pathogenic
REVEL	0.474	indeterminate
SaProt	LLR -15.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00503% Admixed American · 3/59,680 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.00155% 25/1,609,616 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00503%	19,893
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.00321%	31,161
European (non-Finnish)	0.00136%	73,683
South Asian	0.0011%	90,524

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.Pro232Leu
Coding: c.695C>T
MANE Select: NM_000603
Type: single nucleotide variant
Location: chr7:150998559 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20 · 105 PDB
Residue 232: an α-helix; the 'interaction with nosip' region

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

Similar variants

NOS3 p.Pro232= Likely benign ★ same residue
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

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-pro232leu (accessed [today's date]).

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