Is KCND3 p.Arg431His (c.1292G>A) pathogenic?

KCND3 p.Arg431His (c.1292G>A) is classified Conflicting classifications of pathogenicity in KCND3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.1721); Ultra-rare (popmax 0.0227%, afr); Associated with spinocerebellar ataxia type 19/22.

What condition is associated with KCND3 p.Arg431His (c.1292G>A)?

KCND3 p.Arg431His (c.1292G>A) is associated with spinocerebellar ataxia type 19/22, Brugada syndrome 9 (ClinVar).

How common is KCND3 p.Arg431His (c.1292G>A) in the general population?

KCND3 p.Arg431His (c.1292G>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

How is Spinocerebellar ataxia type 19/22 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KCND3 p.Arg431His (c.1292G>A)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

KCND3 p.Arg431His

c.1292G>A · rs771703569 · VCV519484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 19/22

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -12.69	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 4,707 bp · p 0.024 · regional, not allelic
Overall
CADD	30.0	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 0.0227% African / African-American · 17/74,896 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00719% 116/1,613,260 alleles · ultra-rare exomes 95/1,461,074 · genomes 21/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
East Asian	0.0134%	7,483
European (non-Finnish)	0.00729%	13,719
Remaining individualsnot grpmax-eligible	0.0064%	15,616
South Asian	0.00221%	45,341
Admixed American	0.00167%	59,950

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: KCND3
Protein: p.Arg431His
Coding: c.1292G>A
MANE Select: NM_001378969
dbSNP: rs771703569
Type: single nucleotide variant
Location: chr1:111780769 (GRCh38)
Gene constraint: LOEUF 0.303 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.32 · 6 PDB
Residue 431: an α-helix

Full KCND3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 19/22 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Brugada syndrome 9

For Spinocerebellar ataxia type 19/22 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

KCND3 p.Arg431Cys Uncertain significance ★★ ⚠ same residue
KCND3 p.Arg431Leu Uncertain significance ★ ⚠ same residue
KCND3 p.Arg431Pro Uncertain significance ★ ⚠ same residue
KCND3 p.Arg290Gln Likely pathogenic ★★ same condition
KCND3 p.Gly384Ser Pathogenic/Likely pathogenic ★★ same condition
KCND3 p.Pro375Ser Pathogenic/Likely pathogenic ★★ same condition
KCND3 p.Thr377Met Pathogenic ★★ same condition
KCND3 p.Val392Ile 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/kcnd3-p-arg431his (accessed [today's date]).

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