Is NONO p.Pro451Ser (c.1351C>T) pathogenic?

NONO p.Pro451Ser (c.1351C>T) is classified Uncertain significance in NONO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-17). AlphaMissense: likely benign (0.0838); Very rare (popmax 0.00218%, amr); Associated with NONO-related disorder.

What condition is associated with NONO p.Pro451Ser (c.1351C>T)?

NONO p.Pro451Ser (c.1351C>T) is associated with NONO-related disorder (ClinVar).

How common is NONO p.Pro451Ser (c.1351C>T) in the general population?

NONO p.Pro451Ser (c.1351C>T) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about NONO p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

NONO p.Pro451Ser

c.1351C>T · rs776530967 · VCV2628862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NONO-related disorder

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.54	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 5.8	GERP 2, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 3,077 bp · p 2.4e-12 · regional, not allelic
Overall
CADD	17.8	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 0.00218% Admixed American · 1/45,966 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000826% 10/1,211,296 alleles · very rare exomes 10/1,097,640 · genomes 0/113,656 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00218%	45,966
European (non-Finnish)	0.00101%	99,453

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: NONO
Protein: p.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_007363
dbSNP: rs776530967
Type: single nucleotide variant
Location: chrX:71300011 (GRCh38)
Structure: AlphaFold pLDDT 77.76 · 9 PDB
Residue 451: the 'disordered' region

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

Disease context

NONO-related disorder

Similar variants

NONO p.Arg202Trp Uncertain significance ★★ ⚠ same condition
NONO c.1131+1G>T Likely pathogenic ★ same condition
NONO p.Gly372Ter Likely pathogenic ★ same condition
NONO p.Glu354Asp Uncertain significance ⚠ same condition
NONO p.Pro40Ser Uncertain significance ⚠ same condition
NONO c.348+2_348+15del Pathogenic ★ same condition
NONO c.651-1G>C Likely pathogenic ★★ same type
NONO p.Ala377= Pathogenic ★★ 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/nono-p-pro451ser (accessed [today's date]).

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