Is NR5A2 p.Pro244Arg (c.731C>G) pathogenic?

NR5A2 p.Pro244Arg (c.731C>G) is classified Uncertain significance in NR5A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-23). AlphaMissense: likely pathogenic (0.6755); Very rare (popmax 0.000339%, nfe).

How common is NR5A2 p.Pro244Arg (c.731C>G) in the general population?

NR5A2 p.Pro244Arg (c.731C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about NR5A2 p.Pro244Arg (c.731C>G)?

AlphaMissense predicts likely pathogenic (score 0.6755) — an in-silico prediction, not a clinical call.

NR5A2 p.Pro244Arg

c.731C>G · rs749157454 · VCV2279562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6755	likely pathogenic
REVEL	0.701	pathogenic-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 126 kb · p 0.0027 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,042 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,196 alleles · very rare exomes 4/1,461,886 · genomes 0/152,310 · 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: NR5A2
Protein: p.Pro244Arg
Coding: c.731C>G
MANE Select: NM_205860
dbSNP: rs749157454
Type: single nucleotide variant
Location: chr1:200048439 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 73.05 · 28 PDB

Full NR5A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NR5A2 c.464-5A>C Likely benign ★★ same type
NR5A2 p.Arg333Pro Benign/Likely benign ★★ ⚠ same type
NR5A2 p.Lys111= Benign ★★ same type
NR5A2 p.Ala299Val Uncertain significance ★ ⚠ same type
NR5A2 p.Ala480Thr Uncertain significance ★ ⚠ same type
NR5A2 p.Arg137Cys Uncertain significance ★ ⚠ same type
NR5A2 p.Arg142His Uncertain significance ★ ⚠ same type
NR5A2 p.Arg267Trp Uncertain significance ★ ⚠ same type

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/nr5a2-p-pro244arg (accessed [today's date]).

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