Is KCNC3 p.Arg565Trp (c.1693C>T) pathogenic?

KCNC3 p.Arg565Trp (c.1693C>T) is classified Uncertain significance in KCNC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-20). AlphaMissense: likely pathogenic (0.9215); Very rare (popmax 0.00446%, eas).

How common is KCNC3 p.Arg565Trp (c.1693C>T) in the general population?

KCNC3 p.Arg565Trp (c.1693C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about KCNC3 p.Arg565Trp (c.1693C>T)?

AlphaMissense predicts likely pathogenic (score 0.9215) — an in-silico prediction, not a clinical call.

KCNC3 p.Arg565Trp

c.1693C>T · rs750349505 · VCV424152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9215	likely pathogenic
REVEL	0.526	indeterminate
SaProt	LLR -13.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,038 bp · p 0.056 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,842 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000936% 15/1,603,126 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,421
African / African-American	0.00267%	37,453
Finnishnot grpmax-eligible	0.00183%	54,620
European (non-Finnish)	0.000848%	117,906

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.Arg565Trp
Coding: c.1693C>T
MANE Select: NM_004977
dbSNP: rs750349505
Type: single nucleotide variant
Location: chr19:50323260 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 565: the 'disordered' region

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

Similar variants

KCNC3 p.Arg565Gln Uncertain significance ★ ⚠ same residue
KCNC3 p.Arg565Pro Uncertain significance ★ ⚠ same residue
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

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-arg565trp (accessed [today's date]).

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