Is KCNC3 p.Pro587Arg (c.1760C>G) pathogenic?

KCNC3 p.Pro587Arg (c.1760C>G) is classified Conflicting classifications of pathogenicity in KCNC3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-03). AlphaMissense: likely benign (0.139); Ultra-rare (popmax 0.069%, mid); Associated with Inborn genetic diseases.

What condition is associated with KCNC3 p.Pro587Arg (c.1760C>G)?

KCNC3 p.Pro587Arg (c.1760C>G) is associated with Inborn genetic diseases (ClinVar).

How common is KCNC3 p.Pro587Arg (c.1760C>G) in the general population?

KCNC3 p.Pro587Arg (c.1760C>G) is ultra-rare (popmax 0.069%, mid) (gnomAD).

What do computational predictors say about KCNC3 p.Pro587Arg (c.1760C>G)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

KCNC3 p.Pro587Arg

c.1760C>G · rs554197864 · VCV2886694

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.069%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -8.81	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 6.9	GERP 0.14, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,038 bp · p 0.056 · regional, not allelic
Overall
CADD	22.3	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 0.069% Middle Eastern · 3/4,350 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.00348% 53/1,523,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.069%	1,450
South Asian	0.0275%	3,640
European (non-Finnish)	0.0022%	45,435
Admixed American	0.00196%	51,034
Remaining individualsnot grpmax-eligible	0.00168%	59,398

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.Pro587Arg
Coding: c.1760C>G
MANE Select: NM_004977
dbSNP: rs554197864
Type: single nucleotide variant
Location: chr19:50323193 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 587: 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.Pro587Leu Benign/Likely benign ★★ same residue
KCNC3 p.Pro587= 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-pro587arg (accessed [today's date]).

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