Is NOBOX p.Pro492= (c.1476G>A) pathogenic?

NOBOX p.Pro492= (c.1476G>A) is classified Likely benign in NOBOX (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-31). Very rare (popmax 0.00589%, amr); Associated with Inborn genetic diseases.

What condition is associated with NOBOX p.Pro492= (c.1476G>A)?

NOBOX p.Pro492= (c.1476G>A) is associated with Inborn genetic diseases (ClinVar).

How common is NOBOX p.Pro492= (c.1476G>A) in the general population?

NOBOX p.Pro492= (c.1476G>A) is very rare (popmax 0.00589%, amr) (gnomAD).

NOBOX p.Pro492=

c.1476G>A · VCV3357497

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00589%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.8	GERP -2.5
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00589% Admixed American · 3/50,964 alleles

Filtering AF 0.00156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00202% 31/1,536,874 alleles · very rare exomes 29/1,384,706 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0153%	6,516
Admixed Americangrpmax	0.00589%	16,988
Remaining individualsnot grpmax-eligible	0.00333%	29,998
African / African-American	0.00274%	36,515
East Asian	0.00244%	40,918
South Asian	0.00238%	42,014
European (non-Finnish)	0.00122%	81,913

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NOBOX
Protein: p.Pro492=
Coding: c.1476G>A
MANE Select: NM_001436401
Type: single nucleotide variant
Location: chr7:144397489 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 492: a UniProt-annotated variant site (in pof5; uncertain significance; not statistically significant decrease of nuclear location)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOBOX p.Pro492Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NOBOX p.Arg142Cys Uncertain significance ★★ ⚠ same condition
NOBOX p.Arg218Gln Uncertain significance ★★ ⚠ same condition
NOBOX p.Leu386Val Uncertain significance ★★ ⚠ same condition
NOBOX p.Pro179Leu Uncertain significance ★★ ⚠ same condition
NOBOX p.Pro366Ala Uncertain significance ★★ ⚠ same condition
NOBOX p.Thr375Ile Uncertain significance ★★ ⚠ same condition
NOBOX c.38-292G>C Uncertain significance ★ ⚠ same condition

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/nobox-p-pro492 (accessed [today's date]).

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