Is KCNH2 p.Lys897Arg (c.2690A>G) pathogenic?

KCNH2 p.Lys897Arg (c.2690A>G) is classified Conflicting classifications of pathogenicity in KCNH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.067); Very rare (popmax 0.00638%, afr); Associated with cardiac rhythm disease.

What condition is associated with KCNH2 p.Lys897Arg (c.2690A>G)?

KCNH2 p.Lys897Arg (c.2690A>G) is associated with cardiac rhythm disease, long QT syndrome (ClinVar).

How common is KCNH2 p.Lys897Arg (c.2690A>G) in the general population?

KCNH2 p.Lys897Arg (c.2690A>G) is very rare (popmax 0.00638%, afr) (gnomAD).

What do computational predictors say about KCNH2 p.Lys897Arg (c.2690A>G)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

KCNH2 p.Lys897Arg

c.2690A>G · rs1805123 · VCV2773427

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00638%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP 0.47, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 3,159 bp · p 0.045 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00638% African / African-American · 3/47,048 alleles

Filtering AF 0.00169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000869%

Overall 0.000637% 7/1,098,550 alleles · very rare exomes 1/981,826 · genomes 6/116,724 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00638%	15,683
Finnishnot grpmax-eligible	0.00273%	36,650
Remaining individualsnot grpmax-eligible	0.00247%	40,432
European (non-Finnish)	0.00025%	400,498

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: KCNH2
Protein: p.Lys897Arg
Coding: c.2690A>G
MANE Select: NM_000238
dbSNP: rs1805123
Type: single nucleotide variant
Location: chr7:150948446 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI 0.07 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.94 · 24 PDB
Residue 897: the 'disordered' region; a UniProt-annotated variant site (in)

Full KCNH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiac rhythm disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome

Similar variants

KCNH2 p.Lys897Met Uncertain significance ★★ ⚠ same residue
KCNH2 p.Lys897Gln Uncertain significance ★ ⚠ same residue
KCNH2 p.Lys897Glu Uncertain significance ★ ⚠ same residue
KCNH2 p.Lys897delinsThrAspThr Uncertain significance ★★ same residue
KCNH2 p.Lys897fs Uncertain significance ★★ same residue
KCNH2 p.Lys897Thr Likely benign ★ same residue
KCNH2 c.1129-1G>A Pathogenic ★★ same condition
KCNH2 c.1129-2A>G Pathogenic ★★ same condition

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/kcnh2-p-lys897arg (accessed [today's date]).

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