Is KCNC3 p.Arg698Cys (c.2092C>T) pathogenic?

KCNC3 p.Arg698Cys (c.2092C>T) is classified Uncertain significance in KCNC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: ambiguous (0.3517); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with KCNC3 p.Arg698Cys (c.2092C>T)?

KCNC3 p.Arg698Cys (c.2092C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KCNC3 p.Arg698Cys (c.2092C>T) in the general population?

KCNC3 p.Arg698Cys (c.2092C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about KCNC3 p.Arg698Cys (c.2092C>T)?

AlphaMissense predicts ambiguous (score 0.3517) — an in-silico prediction, not a clinical call.

KCNC3 p.Arg698Cys

c.2092C>T · VCV3532170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3517	ambiguous
REVEL	0.687	pathogenic-leaning
SaProt	LLR -7.55	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -3.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,038 bp · p 0.056 · regional, not allelic
Overall
CADD	24.2	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 0.00659% South Asian · 6/91,056 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000684% 10/1,461,584 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,176
European (non-Finnish)	0.000339%	294,989

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.Arg698Cys
Coding: c.2092C>T
MANE Select: NM_004977
Type: single nucleotide variant
Location: chr19:50320671 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 698: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCNC3 p.Arg698His Benign/Likely benign ★★ ⚠ same residue
KCNC3 p.Arg698Leu Likely benign ★ ⚠ same residue
KCNC3 p.Ala44Ser Uncertain significance ★★ ⚠ same condition
KCNC3 p.Arg417His Uncertain significance ★★ ⚠ same condition
KCNC3 p.Arg625Ser Uncertain significance ★★ ⚠ same condition
KCNC3 p.Asp221His Uncertain significance ★★ ⚠ same condition
KCNC3 p.Cys646Trp Uncertain significance ★★ ⚠ same condition
KCNC3 p.Gln39Pro Uncertain significance ★★ ⚠ same condition

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-arg698cys (accessed [today's date]).

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