Is KCNB1 p.Pro613Ser (c.1837C>T) pathogenic?

KCNB1 p.Pro613Ser (c.1837C>T) is classified Benign/Likely benign in KCNB1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0745); Low-frequency (popmax 2%, nfe); Associated with developmental and epileptic encephalopathy, 26.

What condition is associated with KCNB1 p.Pro613Ser (c.1837C>T)?

KCNB1 p.Pro613Ser (c.1837C>T) is associated with developmental and epileptic encephalopathy, 26 (ClinVar).

How common is KCNB1 p.Pro613Ser (c.1837C>T) in the general population?

KCNB1 p.Pro613Ser (c.1837C>T) is low-frequency (popmax 2%, nfe) (gnomAD).

What do computational predictors say about KCNB1 p.Pro613Ser (c.1837C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

KCNB1 p.Pro613Ser

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1837C>T · rs112735799 · VCV383226

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 26

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 752 bp · p 0.65 · regional, not allelic
Overall
CADD	14.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2% European (non-Finnish) · 23,586/1,180,024 alleles

Filtering AF 1.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 1.68% 27,154/1,614,128 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.66%	38
European (non-Finnish)grpmax	2%	50
Remaining individualsnot grpmax-eligible	1.39%	72
Admixed American	1.01%	99
Amishnot grpmax-eligible	0.987%	101
Middle Eastern	0.396%	253
Ashkenazi Jewishnot grpmax-eligible	0.382%	262
African / African-American	0.32%	313
South Asian	0.00549%	18,216

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: KCNB1
Protein: p.Pro613Ser
Coding: c.1837C>T
MANE Select: NM_004975
dbSNP: rs112735799
Type: single nucleotide variant
Location: chr20:49373723 (GRCh38)
Gene constraint: LOEUF 0.309 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 62.90 · 6 PDB
Residue 613: a UniProt-annotated variant site (in dee26; likely pathogenic); a UniProt-annotated variant site (in dee26; likely pathogenic; also found in a patient with neurodevelopmental disorder)

Full KCNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 26 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

KCNB1 p.Pro613= Likely benign ★ same residue
KCNB1 p.Ala406Val Likely pathogenic ★★ same condition
KCNB1 p.Arg303Gln Likely pathogenic ★★ same condition
KCNB1 p.Arg306Cys Pathogenic ★★ same condition
KCNB1 p.Arg312Cys Pathogenic/Likely pathogenic ★★ same condition
KCNB1 p.Arg312His Pathogenic/Likely pathogenic ★★ same condition
KCNB1 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same condition
KCNB1 p.Arg583Ter 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/kcnb1-p-pro613ser (accessed [today's date]).

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