Is KCNC3 p.Pro334Leu (c.1001C>T) pathogenic?

KCNC3 p.Pro334Leu (c.1001C>T) is classified Uncertain significance in KCNC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-24). AlphaMissense: likely benign (0.1176); Very rare (popmax 0.00801%, afr).

How common is KCNC3 p.Pro334Leu (c.1001C>T) in the general population?

KCNC3 p.Pro334Leu (c.1001C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about KCNC3 p.Pro334Leu (c.1001C>T)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

KCNC3 p.Pro334Leu

c.1001C>T · VCV4739886

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -9.91	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 7.5	GERP -3.7, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 4,754 bp · p 1.6e-15 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00801% African / African-American · 6/74,924 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000806% 13/1,613,786 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
Admixed American	0.00167%	60,008
South Asian	0.0011%	91,086
European (non-Finnish)	0.000424%	235,954

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.Pro334Leu
Coding: c.1001C>T
MANE Select: NM_004977
Type: single nucleotide variant
Location: chr19:50323952 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01

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

Similar variants

KCNC3 p.Pro334Ser Uncertain significance ★ ⚠ same residue
KCNC3 p.Pro334= Likely benign 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-pro334leu (accessed [today's date]).

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