Is KCTD7 p.Arg12Pro (c.35G>C) pathogenic?

KCTD7 p.Arg12Pro (c.35G>C) is classified Uncertain significance in KCTD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-21). AlphaMissense: likely benign (0.093); Very rare (popmax 0.000175%, nfe); Associated with progressive myoclonic epilepsy type 3.

What condition is associated with KCTD7 p.Arg12Pro (c.35G>C)?

KCTD7 p.Arg12Pro (c.35G>C) is associated with progressive myoclonic epilepsy type 3 (ClinVar).

How common is KCTD7 p.Arg12Pro (c.35G>C) in the general population?

KCTD7 p.Arg12Pro (c.35G>C) is very rare (popmax 0.000175%, nfe) (gnomAD).

How is Progressive myoclonic epilepsy type 3 inherited?

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

What do computational predictors say about KCTD7 p.Arg12Pro (c.35G>C)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

KCTD7 p.Arg12Pro

c.35G>C · rs763423181 · VCV1405461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonic epilepsy type 3

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 10 kb · p 5.6e-07 · regional, not allelic
Overall
CADD	23.7	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 0.000175% European (non-Finnish) · 2/1,144,688 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00013% 2/1,538,238 alleles · very rare

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: KCTD7
Protein: p.Arg12Pro
Coding: c.35G>C
MANE Select: NM_153033
dbSNP: rs763423181
Type: single nucleotide variant
Location: chr7:66629099 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67
Residue 12: the 'disordered' region

Full KCTD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive myoclonic epilepsy type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive myoclonic epilepsy type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

KCTD7 c.145-2A>G Likely pathogenic ★★ same condition
KCTD7 p.Ala174Thr Likely pathogenic ★★ ⚠ same condition
KCTD7 p.Arg184Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
KCTD7 p.Arg211Ter Pathogenic/Likely pathogenic ★★ same condition
KCTD7 p.Arg99Ter Pathogenic ★★ same condition
KCTD7 p.Tyr276Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
KCTD7 c.144+3A>G Uncertain significance ★★ same condition
KCTD7 p.Ala124Gly 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/kctd7-p-arg12pro (accessed [today's date]).

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