Is NIPBL p.Pro151= (c.453C>T) pathogenic?

NIPBL p.Pro151= (c.453C>T) is classified Likely benign in NIPBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). Ultra-rare (popmax 0.0378%, sas); Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Pro151= (c.453C>T)?

NIPBL p.Pro151= (c.453C>T) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Pro151= (c.453C>T) in the general population?

NIPBL p.Pro151= (c.453C>T) is ultra-rare (popmax 0.0378%, sas) (gnomAD).

NIPBL p.Pro151=

c.453C>T · rs769152836 · VCV2721834

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0378%, sas)

Conditions

Cornelia de Lange syndrome 1

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 2.7	GERP 1.6, phastCons 1
Overall
CADD	12.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0378% South Asian · 34/89,846 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0243%

Overall 0.00251% 39/1,554,762 alleles · ultra-rare exomes 37/1,402,650 · genomes 2/152,112 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0378%	2,643
Admixed American	0.00501%	19,969
Remaining individualsnot grpmax-eligible	0.00165%	60,510
Finnishnot grpmax-eligible	0.00156%	63,976

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.Pro151=
Coding: c.453C>T
MANE Select: NM_133433
dbSNP: rs769152836
Type: single nucleotide variant
Location: chr5:36961578 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 151: the 'disordered' region

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

Disease context

Cornelia de Lange syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NIPBL p.Pro151Thr Uncertain significance ★ same residue
NIPBL p.Pro151Leu 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

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-pro151 (accessed [today's date]).

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