Is KCNC3 p.Pro566Ser (c.1696C>T) pathogenic?

KCNC3 p.Pro566Ser (c.1696C>T) is classified Uncertain significance in KCNC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-04). AlphaMissense: ambiguous (0.4547); Ultra-rare (popmax 0.0166%, mid).

How common is KCNC3 p.Pro566Ser (c.1696C>T) in the general population?

KCNC3 p.Pro566Ser (c.1696C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about KCNC3 p.Pro566Ser (c.1696C>T)?

AlphaMissense predicts ambiguous (score 0.4547) — an in-silico prediction, not a clinical call.

KCNC3 p.Pro566Ser

c.1696C>T · rs761652328 · VCV1211248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Computational evidence

Protein change
AlphaMissense	0.4547	ambiguous
REVEL	0.469	indeterminate
SaProt	LLR -8.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP -0.27, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,038 bp · p 0.056 · regional, not allelic
Overall
CADD	24.5	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 0.0166% Middle Eastern · 1/6,028 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00406% 65/1,602,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,028
European (non-Finnish)	0.00475%	21,058
African / African-American	0.004%	24,970
Finnishnot grpmax-eligible	0.00371%	26,970
Remaining individualsnot grpmax-eligible	0.00321%	31,168
Admixed American	0.00167%	59,816

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: KCNC3
Protein: p.Pro566Ser
Coding: c.1696C>T
MANE Select: NM_004977
dbSNP: rs761652328
Type: single nucleotide variant
Location: chr19:50323257 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 566: the 'disordered' region

Full KCNC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNC3 p.Arg420His Pathogenic ★★ same type
KCNC3 p.Arg423His Pathogenic ★★ same type
KCNC3 p.Ala295Thr Uncertain significance ★★ ⚠ same type
KCNC3 p.Ala44Ser Uncertain significance ★★ ⚠ same type
KCNC3 p.Ala615Val Uncertain significance ★★ ⚠ same type
KCNC3 p.Ala749Thr Uncertain significance ★★ ⚠ same type
KCNC3 p.Arg417His Uncertain significance ★★ ⚠ same type
KCNC3 p.Arg625Ser Uncertain significance ★★ ⚠ 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/kcnc3-p-pro566ser (accessed [today's date]).

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