Is NYX p.Phe166Ser (c.497T>C) pathogenic?

NYX p.Phe166Ser (c.497T>C) is classified Uncertain significance in NYX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-22). AlphaMissense: likely pathogenic (0.9587); No allele count reported in gnomAD v4.1 (AN 1,090,004).

How common is NYX p.Phe166Ser (c.497T>C) in the general population?

NYX p.Phe166Ser (c.497T>C) is no allele count reported in gnomAD v4.1 (AN 1,090,004) (gnomAD).

What do computational predictors say about NYX p.Phe166Ser (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.9587) — an in-silico prediction, not a clinical call.

NYX p.Phe166Ser

c.497T>C · VCV4744168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9587 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,090,004)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9587	likely pathogenic · top 3% in NYX
REVEL	0.771	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.95, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.84 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 F171S vs ClinVar F166S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,090,004). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NYX
Protein: p.Phe166Ser
Coding: c.497T>C
MANE Select: NM_001378477
Type: single nucleotide variant
Location: chrX:41473965 (GRCh38)
Structure: AlphaFold pLDDT 82.68

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

Similar variants

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
NYX p.Ala151Thr 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-phe166ser (accessed [today's date]).

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