Is KDM5C p.Ser451= (c.1353C>T) pathogenic?

KDM5C p.Ser451= (c.1353C>T) is classified Likely benign in KDM5C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00655%, amr); Associated with Spastic paraplegia.

What condition is associated with KDM5C p.Ser451= (c.1353C>T)?

KDM5C p.Ser451= (c.1353C>T) is associated with Spastic paraplegia (ClinVar).

How common is KDM5C p.Ser451= (c.1353C>T) in the general population?

KDM5C p.Ser451= (c.1353C>T) is very rare (popmax 0.00655%, amr) (gnomAD).

KDM5C p.Ser451=

c.1353C>T · rs199422237 · VCV2660596

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00655%, amr)

Conditions

Spastic paraplegia

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 -5.2	GERP -4.5
Overall
CADD	0.456	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00655% Admixed American · 3/45,784 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000882%

Overall 0.000413% 5/1,209,973 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00655%	15,261
East Asian	0.00296%	33,789
South Asian	0.00176%	56,831

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: KDM5C
Protein: p.Ser451=
Coding: c.1353C>T
MANE Select: NM_004187
dbSNP: rs199422237
Type: single nucleotide variant
Location: chrX:53211545 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 451: a UniProt-annotated variant site (in mrxscj)

Full KDM5C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Ser451Arg Pathogenic same residue
KDM5C c.1243-2A>G Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg681Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg750Trp Likely pathogenic ★★ same condition
KDM5C p.Arg778Ter Pathogenic ★★ same condition
KDM5C p.Gln588Ter Pathogenic ★★ same condition
KDM5C c.4038+6C>G Uncertain significance ★★ same condition
KDM5C p.Ala1085Ser 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/kdm5c-p-ser451 (accessed [today's date]).

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