Is NRIP1 p.Pro696Arg (c.2087C>G) pathogenic?

NRIP1 p.Pro696Arg (c.2087C>G) is classified Uncertain significance in NRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0902); Very rare (popmax 6.85e-05%); Associated with Inborn genetic diseases.

What condition is associated with NRIP1 p.Pro696Arg (c.2087C>G)?

NRIP1 p.Pro696Arg (c.2087C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NRIP1 p.Pro696Arg (c.2087C>G) in the general population?

NRIP1 p.Pro696Arg (c.2087C>G) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about NRIP1 p.Pro696Arg (c.2087C>G)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

NRIP1 p.Pro696Arg

c.2087C>G · VCV4122779

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.48	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 5.2	GERP 0.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,473 bp · p 0.013 · regional, not allelic
Overall
CADD	18.22	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 6.85e-05%

Overall 6.85e-05% 1/1,460,050 alleles · very rare

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.Pro696Arg
Coding: c.2087C>G
MANE Select: NM_003489
Type: single nucleotide variant
Location: chr21:14966106 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 46.10 · 17 PDB
Residue 696: the 'repression domain 2' region

Full NRIP1 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

NRIP1 p.Pro696Ser Uncertain significance ★★ ⚠ same residue
NRIP1 p.Ala1096Gly Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala360Ser Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala36Pro Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala792Val Uncertain significance ★★ ⚠ same condition
NRIP1 p.Arg1082Gly Uncertain significance ★★ ⚠ same condition
NRIP1 p.Arg98Trp Uncertain significance ★★ ⚠ same condition
NRIP1 p.Asn45Asp 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/nrip1-p-pro696arg (accessed [today's date]).

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