Is NFRKB p.Pro166Ser (c.496C>T) pathogenic?

NFRKB p.Pro166Ser (c.496C>T) is classified Uncertain significance in NFRKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1183); Very rare (popmax 0.00848%, nfe).

How common is NFRKB p.Pro166Ser (c.496C>T) in the general population?

NFRKB p.Pro166Ser (c.496C>T) is very rare (popmax 0.00848%, nfe) (gnomAD).

What do computational predictors say about NFRKB p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

NFRKB p.Pro166Ser

c.496C>T · VCV3919379

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 16 kb · p 0.22 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.00848% European (non-Finnish) · 100/1,179,040 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00632% 102/1,612,762 alleles · very rare exomes 100/1,460,558 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00848%	11,790
Remaining individualsnot grpmax-eligible	0.0032%	31,208

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.Pro166Ser
Coding: c.496C>T
MANE Select: NM_001143835
Type: single nucleotide variant
Location: chr11:129885579 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.56 · 4 PDB
Residue 166: 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-pro166ser (accessed [today's date]).

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