Is KCNH2 p.Pro968= (c.2904G>A) pathogenic?

KCNH2 p.Pro968= (c.2904G>A) is classified Benign/Likely benign in KCNH2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.016%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with KCNH2 p.Pro968= (c.2904G>A)?

KCNH2 p.Pro968= (c.2904G>A) is associated with Cardiovascular phenotype, long QT syndrome, cardiac rhythm disease (ClinVar).

How common is KCNH2 p.Pro968= (c.2904G>A) in the general population?

KCNH2 p.Pro968= (c.2904G>A) is ultra-rare (popmax 0.016%, nfe) (gnomAD).

KCNH2 p.Pro968=

c.2904G>A · rs75005975 · VCV200250

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -2.8
Overall
CADD	9.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% European (non-Finnish) · 189/1,177,720 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0128% 206/1,608,250 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.016%	6,231
Admixed American	0.0134%	7,442
Remaining individualsnot grpmax-eligible	0.00643%	15,541
African / African-American	0.004%	24,991
East Asian	0.00224%	44,614
South Asian	0.00111%	90,208

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.Pro968=
Coding: c.2904G>A
MANE Select: NM_000238
dbSNP: rs75005975
Type: single nucleotide variant
Location: chr7:150947667 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI 0.07 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.94 · 24 PDB
Residue 968: the 'disordered' region; a UniProt-annotated variant site (in lqt2; uncertain significance)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome cardiac rhythm disease

Similar variants

KCNH2 p.Pro968Ala Uncertain significance ★★ ⚠ same residue
KCNH2 p.Pro968Leu Uncertain significance ★★ ⚠ same residue
KCNH2 p.Pro968Arg Uncertain significance ★ ⚠ same residue
KCNH2 p.Pro968fs Pathogenic ★★ same residue
KCNH2 p.Pro968Ser Uncertain significance ★ ⚠ same residue
KCNH2 c.1129-1G>A Pathogenic ★★ same condition
KCNH2 c.1129-2A>G Pathogenic ★★ same condition
KCNH2 c.1557+1G>C Pathogenic/Likely 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-pro968 (accessed [today's date]).

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