Is KCNC3 p.Ser8Trp (c.23C>G) pathogenic?

KCNC3 p.Ser8Trp (c.23C>G) is classified Conflicting classifications of pathogenicity in KCNC3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.2835); Rare (popmax 0.23%, eas); Associated with Inborn genetic diseases.

What condition is associated with KCNC3 p.Ser8Trp (c.23C>G)?

KCNC3 p.Ser8Trp (c.23C>G) is associated with Inborn genetic diseases (ClinVar).

How common is KCNC3 p.Ser8Trp (c.23C>G) in the general population?

KCNC3 p.Ser8Trp (c.23C>G) is rare (popmax 0.23%, eas) (gnomAD).

What do computational predictors say about KCNC3 p.Ser8Trp (c.23C>G)?

AlphaMissense predicts likely benign (score 0.2835) — an in-silico prediction, not a clinical call.

KCNC3 p.Ser8Trp

c.23C>G · rs761806977 · VCV447623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2835 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.23%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2835	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.13, phastCons 1
Regional constraint	o/e 1.54	unconstrained · MANE · 204 bp · p 6.7e-07 · regional, not allelic
Overall
CADD	21.3	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 0.23% East Asian · 67/29,158 alleles

Filtering AF 0.186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0131% 172/1,311,688 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.23%	435
Remaining individualsnot grpmax-eligible	0.181%	553
Admixed American	0.0236%	4,239
South Asian	0.00183%	54,640
African / African-American	0.00158%	63,164
European (non-Finnish)	0.000588%	170,098

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.Ser8Trp
Coding: c.23C>G
MANE Select: NM_004977
dbSNP: rs761806977
Type: single nucleotide variant
Location: chr19:50329060 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 8: the 'disordered' region; the 'important for normal n-type inactivation' 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.Ser8Leu Uncertain significance ★★ ⚠ same residue
KCNC3 p.Ser8= 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-ser8trp (accessed [today's date]).

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