Is NOBOX p.Ser449= (c.1347C>T) pathogenic?

NOBOX p.Ser449= (c.1347C>T) is classified Conflicting classifications of pathogenicity in NOBOX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-01). Rare (popmax 0.105%, eas); Associated with premature ovarian failure 5.

What condition is associated with NOBOX p.Ser449= (c.1347C>T)?

NOBOX p.Ser449= (c.1347C>T) is associated with premature ovarian failure 5 (ClinVar).

How common is NOBOX p.Ser449= (c.1347C>T) in the general population?

NOBOX p.Ser449= (c.1347C>T) is rare (popmax 0.105%, eas) (gnomAD).

NOBOX p.Ser449=

c.1347C>T · rs374879171 · VCV359139

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Conditions

premature ovarian failure 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -2.5
Overall
CADD	0.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% East Asian · 43/40,912 alleles

Filtering AF 0.0801% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0714%

Overall 0.0141% 216/1,537,144 alleles · rare exomes 195/1,384,816 · genomes 21/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	951
Middle Eastern	0.0501%	1,995
Admixed American	0.0137%	7,287
European (non-Finnish)	0.0125%	8,020
Remaining individualsnot grpmax-eligible	0.0117%	8,576
African / African-American	0.0109%	9,147
Ashkenazi Jewishnot grpmax-eligible	0.0105%	9,549
South Asian	0.00238%	42,024

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.Ser449=
Coding: c.1347C>T
MANE Select: NM_001436401
dbSNP: rs374879171
Type: single nucleotide variant
Location: chr7:144398358 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 449: 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

premature ovarian failure 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOBOX p.Ser449Arg Uncertain significance ★ ⚠ same residue
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.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-ser449 (accessed [today's date]).

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