Is KCNC2 p.Pro559Ser (c.1675C>T) pathogenic?

KCNC2 p.Pro559Ser (c.1675C>T) is classified Uncertain significance in KCNC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely benign (0.114); Very rare (popmax 0.000254%, nfe).

How common is KCNC2 p.Pro559Ser (c.1675C>T) in the general population?

KCNC2 p.Pro559Ser (c.1675C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about KCNC2 p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts likely benign (score 0.114) — an in-silico prediction, not a clinical call.

KCNC2 p.Pro559Ser

c.1675C>T · VCV3390452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.114 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.114	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -6.51	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 8.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,431 bp · p 0.4 · regional, not allelic
Overall
CADD	20.3	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 0.000254% European (non-Finnish) · 3/1,179,278 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,884 alleles · very rare exomes 3/1,460,822 · genomes 0/152,062 · 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: KCNC2
Protein: p.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_139137
Type: single nucleotide variant
Location: chr12:75048258 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 68.26
Residue 559: the 'disordered' region

Full KCNC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNC2 p.Ala187Thr Uncertain significance ★★ ⚠ same type
KCNC2 p.Ala431Val Uncertain significance ★★ ⚠ same type
KCNC2 p.Cys509Phe Uncertain significance ★★ ⚠ same type
KCNC2 p.Phe382= Benign/Likely benign ★★ same type
KCNC2 p.Arg351Lys Pathogenic ★ same type
KCNC2 p.Glu163Lys Likely pathogenic ★ same type
KCNC2 p.Glu404Lys Likely pathogenic ★ same type
KCNC2 p.Leu394Ser Likely pathogenic ★ 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/kcnc2-p-pro559ser (accessed [today's date]).

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