Is NOBOX p.Phe508= (c.1524T>C) pathogenic?

NOBOX p.Phe508= (c.1524T>C) is classified Uncertain significance in NOBOX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.00192%, nfe); Associated with premature ovarian failure 5.

What condition is associated with NOBOX p.Phe508= (c.1524T>C)?

NOBOX p.Phe508= (c.1524T>C) is associated with premature ovarian failure 5 (ClinVar).

How common is NOBOX p.Phe508= (c.1524T>C) in the general population?

NOBOX p.Phe508= (c.1524T>C) is very rare (popmax 0.00192%, nfe) (gnomAD).

NOBOX p.Phe508=

c.1524T>C · rs1046041630 · VCV911030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00192%, nfe)

Conditions

premature ovarian failure 5

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 0.67	GERP -2.5, phastCons 0.73
Overall
CADD	0.823	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00192% European (non-Finnish) · 22/1,146,890 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00143% 22/1,537,238 alleles · very rare exomes 22/1,384,924 · genomes 0/152,314 · joint denominator

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.Phe508=
Coding: c.1524T>C
MANE Select: NM_001436401
dbSNP: rs1046041630
Type: single nucleotide variant
Location: chr7:144397441 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 508: 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.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
NOBOX c.1118+13C>T Likely benign ★★ 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-phe508 (accessed [today's date]).

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