Is NFIB p.Pro166Arg (c.497C>G) pathogenic?

NFIB p.Pro166Arg (c.497C>G) is classified Uncertain significance in NFIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is NFIB p.Pro166Arg (c.497C>G) in the general population?

NFIB p.Pro166Arg (c.497C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFIB p.Pro166Arg (c.497C>G)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

NFIB p.Pro166Arg

c.497C>G · VCV4055925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 10% in NFIB
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -15.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 6,464 bp · p 5.1e-15 · regional, not allelic
Overall
CADD	34.0	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

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: NFIB
Protein: p.Pro166Arg
Coding: c.497C>G
MANE Select: NM_001190737
Type: single nucleotide variant
Location: chr9:14307054 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.17 · 2 PDB
Residue 166: a DNA-binding region; a UniProt-annotated variant site (in macid)

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

Similar variants

NFIB p.Arg301Ter Pathogenic/Likely pathogenic ★★ same type
NFIB p.Arg37Ter Pathogenic ★★ same type
NFIB p.Arg39Cys Pathogenic/Likely pathogenic ★★ same type
NFIB p.Arg48Ter Pathogenic/Likely pathogenic ★★ same type
NFIB p.Arg89Ter Pathogenic/Likely pathogenic ★★ same type
NFIB p.Gln123Ter Likely pathogenic ★★ same type
NFIB p.Leu132Pro Pathogenic/Likely pathogenic ★★ same type
NFIB p.Lys126Glu 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/nfib-p-pro166arg (accessed [today's date]).

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