Is NRIP1 p.Pro519Ser (c.1555C>T) pathogenic?

NRIP1 p.Pro519Ser (c.1555C>T) is classified Uncertain significance in NRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0653); Very rare (popmax 0.00119%, nfe).

How common is NRIP1 p.Pro519Ser (c.1555C>T) in the general population?

NRIP1 p.Pro519Ser (c.1555C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about NRIP1 p.Pro519Ser (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

NRIP1 p.Pro519Ser

c.1555C>T · rs764759333 · VCV1920141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.12	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	GERP 1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,473 bp · p 0.013 · regional, not allelic
Overall
CADD	15.71	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 0.00119% European (non-Finnish) · 14/1,179,990 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,938 alleles · very rare exomes 11/1,461,826 · genomes 3/152,112 · 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.Pro519Ser
Coding: c.1555C>T
MANE Select: NM_003489
dbSNP: rs764759333
Type: single nucleotide variant
Location: chr21:14966638 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 46.10 · 17 PDB
Residue 519: the 'repression domain 2' region

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

Similar variants

NRIP1 p.Pro519Leu Uncertain significance ★ ⚠ 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-pro519ser (accessed [today's date]).

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