Is NFRKB p.Pro754Ala (c.2260C>G) pathogenic?

NFRKB p.Pro754Ala (c.2260C>G) is classified Uncertain significance in NFRKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-04). AlphaMissense: likely benign (0.0542); Absent from gnomAD v4.1.

How common is NFRKB p.Pro754Ala (c.2260C>G) in the general population?

NFRKB p.Pro754Ala (c.2260C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFRKB p.Pro754Ala (c.2260C>G)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

NFRKB p.Pro754Ala

c.2260C>G · VCV4119510

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 0.75, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,797 bp · p 0.071 · regional, not allelic
Overall
CADD	22.7	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NFRKB
Protein: p.Pro754Ala
Coding: c.2260C>G
MANE Select: NM_001143835
Type: single nucleotide variant
Location: chr11:129874132 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.56 · 4 PDB
Residue 754: the 'disordered' region

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

Similar variants

NFRKB p.Arg792Gln Uncertain significance ★★ ⚠ same type
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-pro754ala (accessed [today's date]).

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