Is NIPBL p.Phe42= (c.126T>C) pathogenic?

NIPBL p.Phe42= (c.126T>C) is classified Conflicting classifications of pathogenicity in NIPBL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-07-25). Ultra-rare (popmax 0.0111%, nfe); Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Phe42= (c.126T>C)?

NIPBL p.Phe42= (c.126T>C) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Phe42= (c.126T>C) in the general population?

NIPBL p.Phe42= (c.126T>C) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

NIPBL p.Phe42=

c.126T>C · rs727504046 · VCV167359

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -0.48, phastCons 1
Overall
CADD	9.533	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 131/1,179,912 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00874% 141/1,613,908 alleles · ultra-rare exomes 138/1,461,672 · genomes 3/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,007
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00534%	18,733

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.Phe42=
Coding: c.126T>C
MANE Select: NM_133433
dbSNP: rs727504046
Type: single nucleotide variant
Location: chr5:36955533 (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

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

Similar variants

NIPBL p.Phe42fs Likely pathogenic ★ 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-phe42 (accessed [today's date]).

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