Is KCNC3 p.Pro58Leu (c.173C>T) pathogenic?

KCNC3 p.Pro58Leu (c.173C>T) is classified Uncertain significance in KCNC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-27). AlphaMissense: likely benign (0.1152); Ultra-rare (popmax 0.0119%, eas).

How common is KCNC3 p.Pro58Leu (c.173C>T) in the general population?

KCNC3 p.Pro58Leu (c.173C>T) is ultra-rare (popmax 0.0119%, eas) (gnomAD).

What do computational predictors say about KCNC3 p.Pro58Leu (c.173C>T)?

AlphaMissense predicts likely benign (score 0.1152) — an in-silico prediction, not a clinical call.

KCNC3 p.Pro58Leu

c.173C>T · rs2123547321 · VCV1517239

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1152	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -8.53	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 4.2	GERP -3.1, phastCons 1
Regional constraint	o/e 1.54	unconstrained · MANE · 204 bp · p 6.7e-07 · regional, not allelic
Overall
CADD	21.4	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 0.0119% East Asian · 1/8,426 alleles

Filtering AF 0.000123% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.3e-05%

Overall 0.000656% 5/762,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0119%	8,426
European (non-Finnish)	0.000526%	190,161

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.Pro58Leu
Coding: c.173C>T
MANE Select: NM_004977
dbSNP: rs2123547321
Type: single nucleotide variant
Location: chr19:50328910 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 58: 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

Similar variants

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
KCNC3 p.Arg417His Uncertain significance ★★ ⚠ same type
KCNC3 p.Arg625Ser 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-pro58leu (accessed [today's date]).

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