Is NIPBL p.Ser129Pro (c.385T>C) pathogenic?

NIPBL p.Ser129Pro (c.385T>C) is classified Uncertain significance in NIPBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-22). AlphaMissense: likely benign (0.1248); Very rare (popmax 0.00267%, afr); Associated with Cornelia de Lange syndrome 1.

What condition is associated with NIPBL p.Ser129Pro (c.385T>C)?

NIPBL p.Ser129Pro (c.385T>C) is associated with Cornelia de Lange syndrome 1 (ClinVar).

How common is NIPBL p.Ser129Pro (c.385T>C) in the general population?

NIPBL p.Ser129Pro (c.385T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NIPBL p.Ser129Pro (c.385T>C)?

AlphaMissense predicts likely benign (score 0.1248) — an in-silico prediction, not a clinical call.

NIPBL p.Ser129Pro

c.385T>C · rs141976717 · VCV2038735

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cornelia de Lange syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1248	likely benign
REVEL	0.302	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.0044 · regional, not allelic
Overall
CADD	21.9	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 0.00267% African / African-American · 2/74,894 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000745% 12/1,611,334 alleles · very rare exomes 10/1,459,138 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,447
East Asian	0.00223%	44,762
European (non-Finnish)	0.000764%	130,855

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.Ser129Pro
Coding: c.385T>C
MANE Select: NM_133433
dbSNP: rs141976717
Type: single nucleotide variant
Location: chr5:36961510 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 129: 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.Ser129Cys 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-ser129pro (accessed [today's date]).

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