Is NIPBL p.Ser421= (c.1263G>A) pathogenic?

NIPBL p.Ser421= (c.1263G>A) is classified Likely benign in NIPBL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-24). Ultra-rare (popmax 0.036%, afr); Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Ser421= (c.1263G>A)?

NIPBL p.Ser421= (c.1263G>A) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Ser421= (c.1263G>A) in the general population?

NIPBL p.Ser421= (c.1263G>A) is ultra-rare (popmax 0.036%, afr) (gnomAD).

NIPBL p.Ser421=

c.1263G>A · rs777731868 · VCV716733

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

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 4.5	GERP 1, phastCons 1
Overall
CADD	13.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/74,928 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00285% 46/1,612,600 alleles · ultra-rare exomes 32/1,460,394 · genomes 14/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,775
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0064%	15,613
South Asian	0.0033%	30,302
European (non-Finnish)	0.000933%	107,193

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.Ser421=
Coding: c.1263G>A
MANE Select: NM_133433
dbSNP: rs777731868
Type: single nucleotide variant
Location: chr5:36976170 (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.Ser421Leu 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-ser421 (accessed [today's date]).

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