Is KCNB2 p.Ser830Arg (c.2490C>A) pathogenic?

KCNB2 p.Ser830Arg (c.2490C>A) is classified Uncertain significance in KCNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1328); Very rare (popmax 0.00754%, nfe).

How common is KCNB2 p.Ser830Arg (c.2490C>A) in the general population?

KCNB2 p.Ser830Arg (c.2490C>A) is very rare (popmax 0.00754%, nfe) (gnomAD).

What do computational predictors say about KCNB2 p.Ser830Arg (c.2490C>A)?

AlphaMissense predicts likely benign (score 0.1328) — an in-silico prediction, not a clinical call.

KCNB2 p.Ser830Arg

c.2490C>A · rs756573146 · VCV2227526

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00754%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1328	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.67, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,423 bp · p 0.23 · regional, not allelic
Overall
CADD	17.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00754% European (non-Finnish) · 89/1,180,006 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00558% 90/1,613,970 alleles · very rare exomes 87/1,461,854 · genomes 3/152,116 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00754%	13,259
Admixed American	0.00167%	59,998

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: KCNB2
Protein: p.Ser830Arg
Coding: c.2490C>A
MANE Select: NM_004770
dbSNP: rs756573146
Type: single nucleotide variant
Location: chr8:72937845 (GRCh38)
Gene constraint: LOEUF 0.354 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.23
Residue 830: the 'disordered' region

Full KCNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNB2 p.Ser830Gly Uncertain significance ★ ⚠ same residue
KCNB2 p.Thr381Ala Likely pathogenic ★★ same type
KCNB2 p.Ser528Pro Uncertain significance ★★ ⚠ same type
KCNB2 c.580-31A>T Benign ★★ same type
KCNB2 c.-93-154A>G Benign ★★ same type
KCNB2 p.Glu657Gly Benign ★★ same type
KCNB2 p.Pro57= Benign ★★ same type
KCNB2 p.Ser625= Benign ★★ same type

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/kcnb2-p-ser830arg (accessed [today's date]).

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