Is NR0B1 p.Pro103Arg (c.308C>G) pathogenic?

NR0B1 p.Pro103Arg (c.308C>G) is classified Uncertain significance in NR0B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). AlphaMissense: likely benign (0.0809); Very rare (popmax 0.00205%, afr); Associated with X-linked adrenal hypoplasia congenita.

What condition is associated with NR0B1 p.Pro103Arg (c.308C>G)?

NR0B1 p.Pro103Arg (c.308C>G) is associated with X-linked adrenal hypoplasia congenita, 46,XY sex reversal 2 (ClinVar).

How common is NR0B1 p.Pro103Arg (c.308C>G) in the general population?

NR0B1 p.Pro103Arg (c.308C>G) is very rare (popmax 0.00205%, afr) (gnomAD).

How is X-linked adrenal hypoplasia congenita inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NR0B1 p.Pro103Arg (c.308C>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

NR0B1 p.Pro103Arg

c.308C>G · rs368742214 · VCV2938164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked adrenal hypoplasia congenita

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.3	GERP -0.6
Regional constraint	o/e 0.95	unconstrained · MANE · 1,073 bp · p 0.37 · regional, not allelic
Overall
CADD	16.77	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00205% African / African-American · 1/48,892 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000255% 3/1,177,050 alleles · very rare exomes 3/1,089,206 · genomes 0/87,844 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00205%	48,892
European (non-Finnish)	0.000227%	441,256

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: NR0B1
Protein: p.Pro103Arg
Coding: c.308C>G
MANE Select: NM_000475
dbSNP: rs368742214
Type: single nucleotide variant
Location: chrX:30309056 (GRCh38)
Structure: AlphaFold pLDDT 60.48 · 1 PDB
Residue 103: the '4 x 67 aa tandem repeats' region

Full NR0B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked adrenal hypoplasia congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 46,XY sex reversal 2

For X-linked adrenal hypoplasia congenita (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

NR0B1 p.Pro103Leu Uncertain significance ★★ ⚠ same residue
NR0B1 p.Pro103Ser Uncertain significance ★ ⚠ same residue
NR0B1 p.Ala258Asp Pathogenic/Likely pathogenic ★★ same condition
NR0B1 p.Arg267Pro Pathogenic/Likely pathogenic ★★ same condition
NR0B1 p.Arg425Gly Pathogenic/Likely pathogenic ★★ same condition
NR0B1 p.Cys109Ter Pathogenic ★★ same condition
NR0B1 p.Gln252Ter Pathogenic ★★ same condition
NR0B1 p.Glu307Ter Pathogenic ★★ 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/nr0b1-p-pro103arg (accessed [today's date]).

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