Is KCNN4 p.Arg330Cys (c.988C>T) pathogenic?

KCNN4 p.Arg330Cys (c.988C>T) is classified Uncertain significance in KCNN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.1072); Very rare (popmax 0.00223%, eas).

How common is KCNN4 p.Arg330Cys (c.988C>T) in the general population?

KCNN4 p.Arg330Cys (c.988C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about KCNN4 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

KCNN4 p.Arg330Cys

c.988C>T · VCV3337202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 1,997 bp · p 0.095 · regional, not allelic
Overall
CADD	23.6	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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,614,186 alleles · very rare exomes 9/1,461,884 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
Finnishnot grpmax-eligible	0.00156%	64,034
European (non-Finnish)	0.000593%	168,577

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: KCNN4
Protein: p.Arg330Cys
Coding: c.988C>T
MANE Select: NM_002250
Type: single nucleotide variant
Location: chr19:43769503 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.55 · 17 PDB
Residue 330: an α-helix; the 'calmodulin-binding' region

Full KCNN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNN4 p.Arg330= Likely benign ★ same residue
KCNN4 p.Arg352His Pathogenic ★★ ⚠ same type
KCNN4 c.256-5G>A Uncertain significance ★★ same type
KCNN4 p.Ala336Val Uncertain significance ★★ ⚠ same type
KCNN4 p.Ala55Val Uncertain significance ★★ ⚠ same type
KCNN4 p.Ala78Val Uncertain significance ★★ ⚠ same type
KCNN4 p.Arg342His Uncertain significance ★★ ⚠ same type
KCNN4 p.Arg97Ser 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/kcnn4-p-arg330cys (accessed [today's date]).

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