Is KCNN1 p.Pro522Arg (c.1565C>G) pathogenic?

KCNN1 p.Pro522Arg (c.1565C>G) is classified Uncertain significance in KCNN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.0617); Very rare (popmax 6.53e-05%).

How common is KCNN1 p.Pro522Arg (c.1565C>G) in the general population?

KCNN1 p.Pro522Arg (c.1565C>G) is very rare (popmax 6.53e-05%) (gnomAD).

What do computational predictors say about KCNN1 p.Pro522Arg (c.1565C>G)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

KCNN1 p.Pro522Arg

c.1565C>G · rs2514785186 · VCV3113445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.53e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -8.14	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 -0.069
Regional constraint	o/e 0.94	unconstrained · MANE · 9,951 bp · p 0.31 · regional, not allelic
Overall
CADD	9.417	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 6.53e-05%

Overall 6.53e-05% 1/1,531,044 alleles · very rare exomes 1/1,378,714 · genomes 0/152,330 · 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: KCNN1
Protein: p.Pro522Arg
Coding: c.1565C>G
MANE Select: NM_001386974
dbSNP: rs2514785186
Type: single nucleotide variant
Location: chr19:17998339 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 78.56
Residue 522: the 'disordered' region

Full KCNN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNN1 p.Ala30= Benign ★★ same type
KCNN1 p.Ala151Thr Uncertain significance ★ ⚠ same type
KCNN1 p.Ala162Thr Uncertain significance ★ ⚠ same type
KCNN1 p.Ala20Thr Uncertain significance ★ ⚠ same type
KCNN1 p.Ala218Val Uncertain significance ★ ⚠ same type
KCNN1 p.Ala418Ser Uncertain significance ★ ⚠ same type
KCNN1 p.Ala418Val Uncertain significance ★ ⚠ same type
KCNN1 p.Ala47Gly 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/kcnn1-p-pro522arg (accessed [today's date]).

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