Is NOBOX p.Pro324fs (c.971del) pathogenic?

NOBOX p.Pro324fs (c.971del) is classified Pathogenic in NOBOX (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-15). Ultra-rare (popmax 0.0429%, nfe).

How common is NOBOX p.Pro324fs (c.971del) in the general population?

NOBOX p.Pro324fs (c.971del) is ultra-rare (popmax 0.0429%, nfe) (gnomAD).

NOBOX p.Pro324fs

c.971del · rs753934412 · VCV957395

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0429%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.6	GERP -2
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0429% European (non-Finnish) · 229/533,534 alleles

Filtering AF 0.0383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.0324% 261/804,716 alleles · ultra-rare exomes 261/709,108 · genomes 0/95,608 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0429%	2,330
Middle Eastern	0.0249%	4,020
East Asian	0.0214%	4,679
Remaining individualsnot grpmax-eligible	0.0203%	4,917
South Asian	0.0118%	8,489
Ashkenazi Jewishnot grpmax-eligible	0.0109%	9,211
African / African-American	0.00923%	10,840
Admixed American	0.00736%	13,587
Finnishnot grpmax-eligible	0.00435%	22,971

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.Pro324fs
Coding: c.971del
MANE Select: NM_001436401
dbSNP: rs753934412
Type: Deletion
Location: chr7:144399097 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 324: a DNA-binding region

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

Similar variants

NOBOX p.Pro324Arg Uncertain significance ★ ⚠ same residue
NOBOX p.Pro324Gln Uncertain significance ★ ⚠ same residue
NOBOX p.Cys380fs Likely pathogenic ★ same type
NOBOX p.Val320fs Pathogenic ★ same type
NOBOX p.Ala519fs Uncertain significance ★ same type
NOBOX p.Cys483fs Uncertain significance ★ same type
NOBOX p.Gly261fs Pathogenic same type
NOBOX p.Phe442fs 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/nobox-p-pro324fs (accessed [today's date]).

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