Is NIPBL p.Arg692Lys (c.2075G>A) pathogenic?

NIPBL p.Arg692Lys (c.2075G>A) is classified Uncertain significance in NIPBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.0688); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Arg692Lys (c.2075G>A)?

NIPBL p.Arg692Lys (c.2075G>A) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Arg692Lys (c.2075G>A) in the general population?

NIPBL p.Arg692Lys (c.2075G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NIPBL p.Arg692Lys (c.2075G>A)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

NIPBL p.Arg692Lys

c.2075G>A · VCV4802722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cornelia de Lange syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.261	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,447 bp · p 0.31 · regional, not allelic
Overall
CADD	5.861	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Arg692Lys
Coding: c.2075G>A
MANE Select: NM_133433
Type: single nucleotide variant
Location: chr5:36985255 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 692: 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.Arg692Thr Uncertain significance ★★ ⚠ same residue
NIPBL p.Arg692Ser 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-arg692lys (accessed [today's date]).

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