Is KCND3 p.Pro625Ser (c.1873C>T) pathogenic?

KCND3 p.Pro625Ser (c.1873C>T) is classified Uncertain significance in KCND3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-16). AlphaMissense: likely benign (0.098); Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with KCND3 p.Pro625Ser (c.1873C>T)?

KCND3 p.Pro625Ser (c.1873C>T) is associated with Cardiovascular phenotype, spinocerebellar ataxia type 19/22 (ClinVar).

How common is KCND3 p.Pro625Ser (c.1873C>T) in the general population?

KCND3 p.Pro625Ser (c.1873C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about KCND3 p.Pro625Ser (c.1873C>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

KCND3 p.Pro625Ser

c.1873C>T · rs2101452061 · VCV1375980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.576	indeterminate
SaProt	LLR -6.15	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 4,707 bp · p 0.024 · regional, not allelic
Overall
CADD	22.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.19e-05% 1/1,614,212 alleles · ultra-rare exomes 1/1,461,876 · genomes 0/152,336 · 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: KCND3
Protein: p.Pro625Ser
Coding: c.1873C>T
MANE Select: NM_001378969
dbSNP: rs2101452061
Type: single nucleotide variant
Location: chr1:111776172 (GRCh38)
Gene constraint: LOEUF 0.303 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.32 · 6 PDB
Residue 625: the 'disordered' region

Full KCND3 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: spinocerebellar ataxia type 19/22

Similar variants

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
KCND3 p.Ala144Thr Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala15Val Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala172Thr Uncertain significance ★★ ⚠ 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-pro625ser (accessed [today's date]).

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