Is NOBOX p.Pro77Ser (c.229C>T) pathogenic?

NOBOX p.Pro77Ser (c.229C>T) is classified Uncertain significance in NOBOX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with NOBOX p.Pro77Ser (c.229C>T)?

NOBOX p.Pro77Ser (c.229C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NOBOX p.Pro77Ser (c.229C>T) in the general population?

NOBOX p.Pro77Ser (c.229C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about NOBOX p.Pro77Ser (c.229C>T)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

NOBOX p.Pro77Ser

c.229C>T · VCV4626269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.24	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 0.32	GERP -0.54
Overall
CADD	0.78	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P162S vs ClinVar P77S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,044 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000434% 7/1,612,940 alleles · very rare exomes 7/1,460,612 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,209
Finnishnot grpmax-eligible	0.00157%	63,698
European (non-Finnish)	8.48e-05%	1,179,363

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.Pro77Ser
Coding: c.229C>T
MANE Select: NM_001436401
Type: single nucleotide variant
Location: chr7:144401406 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.12
Residue 162 UniProt numbering: the 'disordered' region

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

Similar variants

NOBOX p.Arg142Cys Uncertain significance ★★ ⚠ same condition
NOBOX p.Arg218Gln 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
NOBOX p.Thr375Ile Uncertain significance ★★ ⚠ same condition
NOBOX c.38-292G>C Uncertain significance ★ ⚠ same condition
NOBOX c.38-343A>G 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-pro77ser (accessed [today's date]).

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