Is KCNT2 p.Val166Phe (c.496G>T) pathogenic?

KCNT2 p.Val166Phe (c.496G>T) is classified Uncertain significance in KCNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-29). AlphaMissense: likely pathogenic (0.9129); Very rare (popmax 8.51e-05%, nfe).

How common is KCNT2 p.Val166Phe (c.496G>T) in the general population?

KCNT2 p.Val166Phe (c.496G>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about KCNT2 p.Val166Phe (c.496G>T)?

AlphaMissense predicts likely pathogenic (score 0.9129) — an in-silico prediction, not a clinical call.

KCNT2 p.Val166Phe

c.496G>T · rs2148665935 · VCV1310194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9129	likely pathogenic
REVEL	0.291	indeterminate
SaProt	LLR -14.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 5.8, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 143 kb · p 2.3e-07 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.51e-05% European (non-Finnish) · 1/1,174,918 alleles

Overall 6.23e-05% 1/1,606,300 alleles · very rare exomes 1/1,454,236 · genomes 0/152,064 · joint denominator

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: KCNT2
Protein: p.Val166Phe
Coding: c.496G>T
MANE Select: NM_198503
dbSNP: rs2148665935
Type: single nucleotide variant
Location: chr1:196467750 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.42

Full KCNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNT2 p.Ala609Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Ala711Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Arg879Gln Uncertain significance ★★ ⚠ same type
KCNT2 p.Asn29Lys Uncertain significance ★★ ⚠ same type
KCNT2 p.Cys484Phe Uncertain significance ★★ ⚠ same type
KCNT2 p.Leu116Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Leu536Pro Uncertain significance ★★ ⚠ same type
KCNT2 p.Met807Val 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/kcnt2-p-val166phe (accessed [today's date]).

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