Is NIPBL p.Arg792Leu (c.2375G>T) pathogenic?

NIPBL p.Arg792Leu (c.2375G>T) is classified Conflicting classifications of pathogenicity in NIPBL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-02-28). AlphaMissense: ambiguous (0.4233); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NIPBL p.Arg792Leu (c.2375G>T)?

NIPBL p.Arg792Leu (c.2375G>T) is associated with Inborn genetic diseases, Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Arg792Leu (c.2375G>T) in the general population?

NIPBL p.Arg792Leu (c.2375G>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about NIPBL p.Arg792Leu (c.2375G>T)?

AlphaMissense predicts ambiguous (score 0.4233) — an in-silico prediction, not a clinical call.

NIPBL p.Arg792Leu

c.2375G>T · rs376912534 · VCV588832

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4233 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4233	ambiguous
REVEL	0.4	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,447 bp · p 0.31 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,952 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,656 alleles · very rare exomes 8/1,461,606 · genomes 1/152,050 · joint denominator

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.Arg792Leu
Coding: c.2375G>T
MANE Select: NM_133433
dbSNP: rs376912534
Type: single nucleotide variant
Location: chr5:36985555 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 792: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cornelia de Lange syndrome 1

Similar variants

NIPBL p.Arg792Trp Uncertain significance ★★ same residue
NIPBL p.Arg792Pro Conflicting classifications of pathogenicity ★ 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-arg792leu (accessed [today's date]).

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