Is NOBOX p.Asp22= (c.66T>C) pathogenic?

NOBOX p.Asp22= (c.66T>C) is classified Benign in NOBOX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-13). Low-frequency (popmax 2.72%, afr); Associated with premature ovarian failure 5.

What condition is associated with NOBOX p.Asp22= (c.66T>C)?

NOBOX p.Asp22= (c.66T>C) is associated with premature ovarian failure 5 (ClinVar).

How common is NOBOX p.Asp22= (c.66T>C) in the general population?

NOBOX p.Asp22= (c.66T>C) is low-frequency (popmax 2.72%, afr) (gnomAD).

NOBOX p.Asp22=

c.66T>C · rs138463368 · VCV359159

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.72%, afr)

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 -0.46	GERP -2.7
Overall
CADD	0.505	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.72% African / African-American · 2,012/74,098 alleles

Filtering AF 2.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.58%

Overall 0.561% 8,804/1,568,248 alleles · low-frequency exomes 7,113/1,415,988 · genomes 1,691/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.72%	37
Middle Eastern	1.43%	70
Admixed American	0.848%	118
Remaining individualsnot grpmax-eligible	0.818%	122
Ashkenazi Jewishnot grpmax-eligible	0.562%	178
European (non-Finnish)	0.459%	218
South Asian	0.334%	300
Finnishnot grpmax-eligible	0.0131%	7,659

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.Asp22=
Coding: c.66T>C
MANE Select: NM_001436401 · reported on NM_001080413
dbSNP: rs138463368
Type: single nucleotide variant
Location: chr7:144410162 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12

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-asp22 (accessed [today's date]).

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