Is NFIX p.Arg264Trp (c.790C>T) pathogenic?

NFIX p.Arg264Trp (c.790C>T) is classified Uncertain significance in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.7805); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NFIX p.Arg264Trp (c.790C>T)?

NFIX p.Arg264Trp (c.790C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NFIX p.Arg264Trp (c.790C>T) in the general population?

NFIX p.Arg264Trp (c.790C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about NFIX p.Arg264Trp (c.790C>T)?

AlphaMissense predicts likely pathogenic (score 0.7805) — an in-silico prediction, not a clinical call.

NFIX p.Arg264Trp

c.790C>T · VCV3405212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7805	likely pathogenic
REVEL	0.455	indeterminate
SaProt	LLR -14.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -0.74, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 56 kb · p 9.3e-13 · regional, not allelic
Overall
CADD	32.0	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,886 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,990 alleles · very rare exomes 2/1,461,664 · genomes 0/152,326 · 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: NFIX
Protein: p.Arg264Trp
Coding: c.790C>T
MANE Select: NM_001365902
Type: single nucleotide variant
Location: chr19:13073998 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 264: the 'disordered' region

Full NFIX 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

NFIX p.Arg264Leu Uncertain significance ★ ⚠ same residue
NFIX c.559+1G>A Pathogenic ★★ same condition
NFIX p.Glu52Ter Pathogenic/Likely pathogenic ★★ same condition
NFIX p.Leu120Arg Uncertain significance ★★ ⚠ same condition
NFIX p.Leu261Met Uncertain significance ★★ ⚠ same condition
NFIX p.Ile202Val Likely benign ★★ same condition
NFIX c.28-16G>A Conflicting classifications of pathogenicity ★ same condition
NFIX c.955+3A>G 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/nfix-p-arg264trp (accessed [today's date]).

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