Is KCNH2 p.Phe656= (c.1968C>T) pathogenic?

KCNH2 p.Phe656= (c.1968C>T) is classified Likely benign in KCNH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-12). Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

What condition is associated with KCNH2 p.Phe656= (c.1968C>T)?

KCNH2 p.Phe656= (c.1968C>T) is associated with Cardiovascular phenotype, long QT syndrome, cardiac rhythm disease (ClinVar).

How common is KCNH2 p.Phe656= (c.1968C>T) in the general population?

KCNH2 p.Phe656= (c.1968C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

KCNH2 p.Phe656=

c.1968C>T · rs1238904019 · VCV1152898

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.45	GERP -2.9, phastCons 0.97
Overall
CADD	13.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00136% 22/1,611,810 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,416
European (non-Finnish)	0.00144%	69,352
African / African-American	0.00133%	74,922
South Asian	0.0011%	91,038

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.Phe656=
Coding: c.1968C>T
MANE Select: NM_000238
dbSNP: rs1238904019
Type: single nucleotide variant
Location: chr7:150951098 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI 0.07 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.94 · 24 PDB
Residue 656: a UniProt-annotated variant site (in lqt2; uncertain significance); an α-helix

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.Phe656Leu Uncertain significance ★ ⚠ same residue
KCNH2 p.Phe656_Ile663del Pathogenic ★ 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
KCNH2 c.1945+1G>A Likely pathogenic ★★ same condition
KCNH2 c.1945+6T>C Pathogenic/Likely pathogenic ★★ same condition
KCNH2 c.1946-2A>C 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-phe656 (accessed [today's date]).

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