Is KCNB2 p.Ser554Pro (c.1660T>C) pathogenic?

KCNB2 p.Ser554Pro (c.1660T>C) is classified Uncertain significance in KCNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0586); Very rare (popmax 0.000169%, nfe).

How common is KCNB2 p.Ser554Pro (c.1660T>C) in the general population?

KCNB2 p.Ser554Pro (c.1660T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about KCNB2 p.Ser554Pro (c.1660T>C)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

KCNB2 p.Ser554Pro

c.1660T>C · rs1806919541 · VCV2291994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.37	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 -1.8	GERP -4.6
Regional constraint	o/e 0.95	unconstrained · MANE · 1,423 bp · p 0.23 · regional, not allelic
Overall
CADD	1.157	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 0.000169% European (non-Finnish) · 2/1,179,988 alleles

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

Overall 0.000124% 2/1,613,968 alleles · very rare exomes 2/1,461,866 · genomes 0/152,102 · 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: KCNB2
Protein: p.Ser554Pro
Coding: c.1660T>C
MANE Select: NM_004770
dbSNP: rs1806919541
Type: single nucleotide variant
Location: chr8:72937015 (GRCh38)
Gene constraint: LOEUF 0.354 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.23
Residue 554: the 'disordered' region

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

Similar variants

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
KCNB2 p.Thr52= 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-ser554pro (accessed [today's date]).

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