Is NIPBL p.Val66= (c.198C>G) pathogenic?

NIPBL p.Val66= (c.198C>G) is classified Benign/Likely benign in NIPBL (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-01). Rare (popmax 0.208%, amr); Associated with Inborn genetic diseases.

What condition is associated with NIPBL p.Val66= (c.198C>G)?

NIPBL p.Val66= (c.198C>G) is associated with Inborn genetic diseases, Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Val66= (c.198C>G) in the general population?

NIPBL p.Val66= (c.198C>G) is rare (popmax 0.208%, amr) (gnomAD).

NIPBL p.Val66=

c.198C>G · rs146033170 · VCV96332

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.208%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -1.2, phastCons 0.99
Overall
CADD	7.731	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.208% Admixed American · 125/60,014 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0402% 648/1,613,916 alleles · rare exomes 597/1,461,662 · genomes 51/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.208%	480
Ashkenazi Jewishnot grpmax-eligible	0.135%	740
Remaining individualsnot grpmax-eligible	0.0496%	2,016
European (non-Finnish)	0.038%	2,634
Middle Eastern	0.0165%	6,060
African / African-American	0.004%	25,005

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: NIPBL
Protein: p.Val66=
Coding: c.198C>G
MANE Select: NM_133433
dbSNP: rs146033170
Type: single nucleotide variant
Location: chr5:36955605 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cornelia de Lange syndrome 1

Similar variants

NIPBL p.Val66Ala Uncertain significance ★ same residue
NIPBL c.3304+1G>A Pathogenic/Likely pathogenic ★★ same condition
NIPBL c.358+1G>T Pathogenic ★★ same condition
NIPBL c.3855+5G>A Pathogenic/Likely pathogenic ★★ same condition
NIPBL c.5329-15A>G Pathogenic ★★ same condition
NIPBL c.5575-1G>A Likely pathogenic ★★ same condition
NIPBL c.5709+1G>A Pathogenic/Likely pathogenic ★★ same condition
NIPBL c.5808+1G>A Pathogenic ★★ same condition

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/nipbl-p-val66 (accessed [today's date]).

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