Is NIPBL p.Ser698Pro (c.2092T>C) pathogenic?

NIPBL p.Ser698Pro (c.2092T>C) is classified Likely benign in NIPBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). AlphaMissense: likely benign (0.0825); Ultra-rare (popmax 0.0297%, sas); Associated with Inborn genetic diseases.

What condition is associated with NIPBL p.Ser698Pro (c.2092T>C)?

NIPBL p.Ser698Pro (c.2092T>C) is associated with Inborn genetic diseases, Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Ser698Pro (c.2092T>C) in the general population?

NIPBL p.Ser698Pro (c.2092T>C) is ultra-rare (popmax 0.0297%, sas) (gnomAD).

What do computational predictors say about NIPBL p.Ser698Pro (c.2092T>C)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

NIPBL p.Ser698Pro

c.2092T>C · rs550141620 · VCV2409363

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.227	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 -2.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,447 bp · p 0.31 · regional, not allelic
Overall
CADD	16.44	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 0.0297% South Asian · 27/91,042 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00167% 27/1,612,878 alleles · ultra-rare exomes 26/1,461,564 · genomes 1/151,314 · 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.Ser698Pro
Coding: c.2092T>C
MANE Select: NM_133433
dbSNP: rs550141620
Type: single nucleotide variant
Location: chr5:36985272 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 698: 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.Ser698Ter 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-ser698pro (accessed [today's date]).

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