Is NFKB1 p.Phe420Leu (c.1258T>C) pathogenic?

NFKB1 p.Phe420Leu (c.1258T>C) is classified Uncertain significance in NFKB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely pathogenic (0.8642); Very rare (popmax 6.2e-05%).

How common is NFKB1 p.Phe420Leu (c.1258T>C) in the general population?

NFKB1 p.Phe420Leu (c.1258T>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about NFKB1 p.Phe420Leu (c.1258T>C)?

AlphaMissense predicts likely pathogenic (score 0.8642) — an in-silico prediction, not a clinical call.

NFKB1 p.Phe420Leu

c.1258T>C · rs2476492182 · VCV2075384

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8642	likely pathogenic
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,055 bp · p 0.92 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F419L vs ClinVar F420L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,611,946 alleles · very rare exomes 1/1,459,620 · 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: NFKB1
Protein: p.Phe420Leu
Coding: c.1258T>C
MANE Select: NM_003998
dbSNP: rs2476492182
Type: single nucleotide variant
Location: chr4:102594939 (GRCh38)
Gene constraint: LOEUF 0.178 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.84 · 15 PDB

Full NFKB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NFKB1 c.159+1G>A Pathogenic/Likely pathogenic ★★ same type
NFKB1 c.1753-1G>C Likely pathogenic ★★ same type
NFKB1 c.407+1G>A Pathogenic/Likely pathogenic ★★ same type
NFKB1 c.407+2T>G Pathogenic/Likely pathogenic ★★ same type
NFKB1 c.835+2T>C Likely pathogenic ★★ same type
NFKB1 c.928-1G>A Likely pathogenic ★★ same type
NFKB1 p.Arg157Ter Pathogenic ★★ same type
NFKB1 p.Arg284Ter Pathogenic/Likely pathogenic ★★ 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/nfkb1-p-phe420leu (accessed [today's date]).

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