Is NIPBL p.Pro281Arg (c.842C>G) pathogenic?

NIPBL p.Pro281Arg (c.842C>G) is classified Uncertain significance in NIPBL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.6842); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Pro281Arg (c.842C>G)?

NIPBL p.Pro281Arg (c.842C>G) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Pro281Arg (c.842C>G) in the general population?

NIPBL p.Pro281Arg (c.842C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NIPBL p.Pro281Arg (c.842C>G)?

AlphaMissense predicts likely pathogenic (score 0.6842) — an in-silico prediction, not a clinical call.

NIPBL p.Pro281Arg

c.842C>G · rs2479098227 · VCV2702116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6842 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cornelia de Lange syndrome 1

Computational evidence

Protein change
AlphaMissense	0.6842	likely pathogenic
REVEL	0.539	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.0044 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NIPBL
Protein: p.Pro281Arg
Coding: c.842C>G
MANE Select: NM_133433
dbSNP: rs2479098227
Type: single nucleotide variant
Location: chr5:36972015 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 281: 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.Pro281= Likely benign ★ same residue
NIPBL p.Pro281Ala 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-pro281arg (accessed [today's date]).

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