Is NOS3 p.Phe286Cys (c.857T>G) pathogenic?

NOS3 p.Phe286Cys (c.857T>G) is classified Uncertain significance in NOS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.9715); Absent from gnomAD v4.1.

How common is NOS3 p.Phe286Cys (c.857T>G) in the general population?

NOS3 p.Phe286Cys (c.857T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOS3 p.Phe286Cys (c.857T>G)?

AlphaMissense predicts likely pathogenic (score 0.9715) — an in-silico prediction, not a clinical call.

NOS3 p.Phe286Cys

c.857T>G · VCV4121597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9715 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9715	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -12.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.89, phastCons 1
Overall
CADD	26.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOS3
Protein: p.Phe286Cys
Coding: c.857T>G
MANE Select: NM_000603
Type: single nucleotide variant
Location: chr7:150998986 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.20 · 105 PDB
Residue 286: 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.Phe286Val Uncertain significance ★ ⚠ 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-phe286cys (accessed [today's date]).

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