Is NOS1 p.Arg98Ser (c.294G>C) pathogenic?

NOS1 p.Arg98Ser (c.294G>C) is classified Uncertain significance in NOS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.9864); Ultra-rare (popmax 0.0181%, nfe).

How common is NOS1 p.Arg98Ser (c.294G>C) in the general population?

NOS1 p.Arg98Ser (c.294G>C) is ultra-rare (popmax 0.0181%, nfe) (gnomAD).

What do computational predictors say about NOS1 p.Arg98Ser (c.294G>C)?

AlphaMissense predicts likely pathogenic (score 0.9864) — an in-silico prediction, not a clinical call.

NOS1 p.Arg98Ser

c.294G>C · rs370576212 · VCV2462273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9864	likely pathogenic · top 10% in NOS1
REVEL	0.271	benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP 0.094, phastCons 0.083
Overall
CADD	18.54	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 0.0181% European (non-Finnish) · 214/1,180,016 alleles

Filtering AF 0.0161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0153%

Overall 0.0137% 221/1,613,964 alleles · ultra-rare exomes 210/1,461,838 · genomes 11/152,126 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0181%	5,514
African / African-American	0.00667%	14,983
Remaining individualsnot grpmax-eligible	0.0032%	31,245

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: NOS1
Protein: p.Arg98Ser
Coding: c.294G>C
MANE Select: NM_000620
dbSNP: rs370576212
Type: single nucleotide variant
Location: chr12:117330776 (GRCh38)
Structure: AlphaFold pLDDT 61.90 · 1 PDB
Residue 98: the 'disordered' region

Full NOS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NANOS1 c.-51G>C Benign ★★ same type
NANOS1 p.Pro34Thr Benign ★★ same type
NOS1 c.3042-6C>T Benign ★★ same type
NOS1 p.Ala1337= Likely benign ★★ same type
NOS1 p.Asp241Asn Benign/Likely benign ★★ same type
NOS1 p.Asp394Ala Benign/Likely benign ★★ same type
NOS1 p.Gly595Ser Benign/Likely benign ★★ same type
NOS1 p.Gly864Asp Likely 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/nos1-p-arg98ser (accessed [today's date]).

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