Is NFIB p.Pro66Ser (c.196C>T) pathogenic?

NFIB p.Pro66Ser (c.196C>T) is classified Benign in NFIB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.179); Low-frequency (popmax 1.62%, sas).

How common is NFIB p.Pro66Ser (c.196C>T) in the general population?

NFIB p.Pro66Ser (c.196C>T) is low-frequency (popmax 1.62%, sas) (gnomAD).

What do computational predictors say about NFIB p.Pro66Ser (c.196C>T)?

AlphaMissense predicts likely benign (score 0.179) — an in-silico prediction, not a clinical call.

NFIB p.Pro66Ser

c.196C>T · VCV4533584

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.179 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.62%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.179	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -11.83	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	33.0	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 1.62% South Asian · 1,477/91,048 alleles

Filtering AF 1.55% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 0.103% 1,656/1,613,944 alleles · low-frequency exomes 1,555/1,461,854 · genomes 101/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.62%	62
Middle Eastern	0.214%	466
Remaining individualsnot grpmax-eligible	0.115%	868
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,973
Admixed American	0.035%	2,857
European (non-Finnish)	0.00483%	20,702
East Asian	0.00223%	44,846

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: NFIB
Protein: p.Pro66Ser
Coding: c.196C>T
MANE Select: NM_001190737
Type: single nucleotide variant
Location: chr9:14307355 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.17 · 2 PDB
Residue 66: 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.Pro66Ala Likely benign ★ ⚠ same residue
NFIB p.Pro66fs Likely pathogenic ★ same residue
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

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-pro66ser (accessed [today's date]).

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