Is NFRKB p.Arg792Leu (c.2375G>T) pathogenic?

NFRKB p.Arg792Leu (c.2375G>T) is classified Uncertain significance in NFRKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.388); Ultra-rare (popmax 0.0165%, mid).

How common is NFRKB p.Arg792Leu (c.2375G>T) in the general population?

NFRKB p.Arg792Leu (c.2375G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NFRKB p.Arg792Leu (c.2375G>T)?

AlphaMissense predicts ambiguous (score 0.388) — an in-silico prediction, not a clinical call.

NFRKB p.Arg792Leu

c.2375G>T · VCV4557353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.388 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.388	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -5.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,797 bp · p 0.071 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00514% 83/1,613,608 alleles · ultra-rare exomes 77/1,461,276 · genomes 6/152,332 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00669%	14,937
Admixed American	0.00333%	30,008
South Asian	0.0011%	91,084

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: NFRKB
Protein: p.Arg792Leu
Coding: c.2375G>T
MANE Select: NM_001143835
Type: single nucleotide variant
Location: chr11:129873920 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.56 · 4 PDB

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

Similar variants

NFRKB p.Arg792Gln Uncertain significance ★★ ⚠ same residue
NFRKB c.641-27A>C Uncertain significance ★ same type
NFRKB p.Ala1057Thr Uncertain significance ★ ⚠ same type
NFRKB p.Ala1118Val Uncertain significance ★ ⚠ same type
NFRKB p.Ala1128Val Uncertain significance ★ ⚠ same type
NFRKB p.Ala1148Pro Uncertain significance ★ ⚠ same type
NFRKB p.Ala1159Ser Uncertain significance ★ ⚠ same type
NFRKB p.Ala230Val 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/nfrkb-p-arg792leu (accessed [today's date]).

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