Is NOBOX p.Pro399Ser (c.1195C>T) pathogenic?

NOBOX p.Pro399Ser (c.1195C>T) is classified Conflicting classifications of pathogenicity in NOBOX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-10-20). AlphaMissense: likely benign (0.0901); Rare (popmax 0.438%, sas); Associated with Inborn genetic diseases.

What condition is associated with NOBOX p.Pro399Ser (c.1195C>T)?

NOBOX p.Pro399Ser (c.1195C>T) is associated with Inborn genetic diseases, premature ovarian failure 5 (ClinVar).

How common is NOBOX p.Pro399Ser (c.1195C>T) in the general population?

NOBOX p.Pro399Ser (c.1195C>T) is rare (popmax 0.438%, sas) (gnomAD).

What do computational predictors say about NOBOX p.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

NOBOX p.Pro399Ser

c.1195C>T · rs531662858 · VCV359140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.438%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.93	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 1.9	GERP 0.45, phastCons 0.059
Overall
CADD	3.014	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P516S vs ClinVar P399S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.438% South Asian · 368/84,026 alleles

Filtering AF 0.401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.387%

Overall 0.0259% 398/1,536,672 alleles · rare exomes 371/1,384,498 · genomes 27/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.438%	228
Remaining individualsnot grpmax-eligible	0.0433%	2,308
African / African-American	0.0041%	24,362
European (non-Finnish)	8.72e-05%	1,146,696

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.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_001436401
dbSNP: rs531662858
Type: single nucleotide variant
Location: chr7:144398510 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 516 UniProt numbering: 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

Also linked: premature ovarian failure 5

Similar variants

NOBOX p.Arg218Ter Pathogenic ★★ same condition
NOBOX p.Arg142Cys Uncertain significance ★★ ⚠ same condition
NOBOX p.Arg218Gln Uncertain significance ★★ ⚠ same condition
NOBOX p.Arg44Trp Uncertain significance ★★ ⚠ same condition
NOBOX p.Gly26Arg 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

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-pro399ser (accessed [today's date]).

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