Is NRIP1 p.Pro233Arg (c.698C>G) pathogenic?

NRIP1 p.Pro233Arg (c.698C>G) is classified Uncertain significance in NRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.4288); Very rare (popmax 0.00267%, afr).

How common is NRIP1 p.Pro233Arg (c.698C>G) in the general population?

NRIP1 p.Pro233Arg (c.698C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NRIP1 p.Pro233Arg (c.698C>G)?

AlphaMissense predicts ambiguous (score 0.4288) — an in-silico prediction, not a clinical call.

NRIP1 p.Pro233Arg

c.698C>G · VCV4769082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.4288	ambiguous
REVEL	0.519	indeterminate
SaProt	LLR -7.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,473 bp · p 0.013 · regional, not allelic
Overall
CADD	24.5	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 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,950 alleles · very rare exomes 1/1,461,848 · genomes 1/152,102 · 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: NRIP1
Protein: p.Pro233Arg
Coding: c.698C>G
MANE Select: NM_003489
Type: single nucleotide variant
Location: chr21:14967495 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 46.10 · 17 PDB
Residue 233: the 'interaction with znf366' region; the 'repression domain 1' region

Full NRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NRIP1 p.Pro233= Likely benign ★★ same residue
NRIP1 p.Ala1096Gly Uncertain significance ★★ ⚠ same type
NRIP1 p.Ala360Ser Uncertain significance ★★ ⚠ same type
NRIP1 p.Ala36Pro Uncertain significance ★★ ⚠ same type
NRIP1 p.Ala792Val Uncertain significance ★★ ⚠ same type
NRIP1 p.Arg1082Gly Uncertain significance ★★ ⚠ same type
NRIP1 p.Arg1122Gly Uncertain significance ★★ ⚠ same type
NRIP1 p.Arg98Trp 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/nrip1-p-pro233arg (accessed [today's date]).

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