Is NYNRIN p.Pro663Leu (c.1988C>T) pathogenic?

NYNRIN p.Pro663Leu (c.1988C>T) is classified Uncertain significance in NYNRIN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.087); Rare (popmax 0.38%, mid); Associated with Predisposition to Wilms tumor.

What condition is associated with NYNRIN p.Pro663Leu (c.1988C>T)?

NYNRIN p.Pro663Leu (c.1988C>T) is associated with Predisposition to Wilms tumor (ClinVar).

How common is NYNRIN p.Pro663Leu (c.1988C>T) in the general population?

NYNRIN p.Pro663Leu (c.1988C>T) is rare (popmax 0.38%, mid) (gnomAD).

What do computational predictors say about NYNRIN p.Pro663Leu (c.1988C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

NYNRIN p.Pro663Leu

c.1988C>T · VCV3602686

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.38%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Predisposition to Wilms tumor

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.95	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 1.9	GERP 1.3, phastCons 0.03
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	19.08	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 0.38% Middle Eastern · 23/6,060 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.0213% 343/1,612,878 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.38%	263
Admixed American	0.124%	809
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
Remaining individualsnot grpmax-eligible	0.0753%	1,329
African / African-American	0.024%	4,168
South Asian	0.0132%	7,563
European (non-Finnish)	0.0111%	9,003
East Asian	0.00223%	44,854
Finnishnot grpmax-eligible	0.00156%	63,964

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: NYNRIN
Protein: p.Pro663Leu
Coding: c.1988C>T
MANE Select: NM_025081
Type: single nucleotide variant
Location: chr14:24409782 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.04
Residue 663: the 'disordered' region

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

Disease context

Predisposition to Wilms tumor

Similar variants

NYNRIN p.Ala555Asp Uncertain significance ★★ ⚠ same condition
NYNRIN p.Arg1433Trp Uncertain significance ★★ ⚠ same condition
NYNRIN p.Asp1106Val Uncertain significance ★★ ⚠ same condition
NYNRIN p.Gly1452Arg Uncertain significance ★★ ⚠ same condition
NYNRIN p.Leu1713Pro Uncertain significance ★★ ⚠ same condition
NYNRIN p.Lys259Met Uncertain significance ★★ ⚠ same condition
NYNRIN p.Lys679Gln Uncertain significance ★★ ⚠ same condition
NYNRIN p.Met1786Val 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/nynrin-p-pro663leu (accessed [today's date]).

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