Is NYX p.Pro396Arg (c.1187C>G) pathogenic?

NYX p.Pro396Arg (c.1187C>G) is classified Uncertain significance in NYX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). AlphaMissense: likely benign (0.0713); Ultra-rare (popmax 0.057%, eas).

How common is NYX p.Pro396Arg (c.1187C>G) in the general population?

NYX p.Pro396Arg (c.1187C>G) is ultra-rare (popmax 0.057%, eas) (gnomAD).

What do computational predictors say about NYX p.Pro396Arg (c.1187C>G)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

NYX p.Pro396Arg

c.1187C>G · rs746961966 · VCV2182751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.057%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.096	GERP -2.5
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.84 · regional, not allelic
Overall
CADD	15.08	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P401R vs ClinVar P396R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.057% East Asian · 19/33,328 alleles

Filtering AF 0.0373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.031%

Overall 0.00317% 38/1,197,314 alleles · ultra-rare exomes 36/1,085,949 · genomes 2/111,365 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.057%	1,754
Finnishnot grpmax-eligible	0.00892%	11,209
Remaining individualsnot grpmax-eligible	0.00637%	15,708
European (non-Finnish)	0.00135%	74,134

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: NYX
Protein: p.Pro396Arg
Coding: c.1187C>G
MANE Select: NM_001378477
dbSNP: rs746961966
Type: single nucleotide variant
Location: chrX:41474655 (GRCh38)
Structure: AlphaFold pLDDT 82.68

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

Similar variants

NYX p.Pro396= Conflicting classifications of pathogenicity ★ same residue
NYX p.Asn211Ser Pathogenic/Likely pathogenic ★★ same type
NYX p.Pro170Arg Pathogenic ★★ same type
NYX p.Ser196Ter Pathogenic ★★ same type
NYX p.Ser40Ter Pathogenic/Likely pathogenic ★★ same type
NYX p.Ala113Thr Uncertain significance ★★ same type
NYX p.Ala113Val Uncertain significance ★★ same type
NYX p.Ala123Val 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/nyx-p-pro396arg (accessed [today's date]).

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