Is NIPBL p.Ser604Pro (c.1810T>C) pathogenic?

NIPBL p.Ser604Pro (c.1810T>C) is classified Uncertain significance in NIPBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with NIPBL p.Ser604Pro (c.1810T>C)?

NIPBL p.Ser604Pro (c.1810T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NIPBL p.Ser604Pro (c.1810T>C) in the general population?

NIPBL p.Ser604Pro (c.1810T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NIPBL p.Ser604Pro (c.1810T>C)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

NIPBL p.Ser604Pro

c.1810T>C · VCV4120110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.346	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP 0.03, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,447 bp · p 0.31 · regional, not allelic
Overall
CADD	18.36	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 0.00133% African / African-American · 1/75,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,844 alleles · very rare exomes 3/1,461,628 · genomes 0/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
European (non-Finnish)	0.00017%	589,967

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.Ser604Pro
Coding: c.1810T>C
MANE Select: NM_133433
Type: single nucleotide variant
Location: chr5:36984990 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 604: 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

Similar variants

NIPBL c.771+1G>A Pathogenic ★★ same condition
NIPBL p.Arg1106Ter Pathogenic ★★ same condition
NIPBL p.Arg1814Ter Pathogenic ★★ same condition
NIPBL p.Arg479Ter Pathogenic ★★ same condition
NIPBL p.Ser604fs Likely pathogenic ★★ same residue
NIPBL p.Ala933Gly Uncertain significance ★★ ⚠ same condition
NIPBL p.Arg1120Ser Uncertain significance ★★ same condition
NIPBL p.Arg2582Gln Uncertain significance ★★ ⚠ 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-ser604pro (accessed [today's date]).

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