Is KCNC3 p.Met77fs (c.228_249del) pathogenic?

KCNC3 p.Met77fs (c.228249del) is classified Uncertain significance in KCNC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-08). Very rare (popmax 8.9e-05%, nfe).

How common is KCNC3 p.Met77fs (c.228_249del) in the general population?

KCNC3 p.Met77fs (c.228_249del) is very rare (popmax 8.9e-05%, nfe) (gnomAD).

KCNC3 p.Met77fs

c.228_249del · rs2123547025 · VCV1312636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.9e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP -3.6, phastCons 1
Region caveats
Repeat context	tandem	(GCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.9e-05% European (non-Finnish) · 1/1,123,470 alleles

Overall 7.47e-05% 1/1,338,258 alleles · very rare

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.Met77fs
Coding: c.228_249del
MANE Select: NM_004977
dbSNP: rs2123547025
Type: Deletion
Location: chr19:50328834 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 77: 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.Arg625fs Uncertain significance ★★ same type
KCNC3 p.Gly209_Ala211del Uncertain significance ★★ same type
KCNC3 p.Val5_Ser8del Uncertain significance ★★ same type
KCNC3 c.*13del Likely benign ★★ same type
KCNC3 p.Ser4fs Pathogenic ★ same type
KCNC3 p.Asp63fs Uncertain significance ★ same type
KCNC3 p.Gly253_Gly263del Uncertain significance ★ same type
KCNC3 p.Gly255fs 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-met77fs (accessed [today's date]).

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