Is KDM5C p.Ser941= (c.2823A>G) pathogenic?

KDM5C p.Ser941= (c.2823A>G) is classified Benign/Likely benign in KDM5C (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-12). Rare (popmax 0.184%, amr); Associated with Spastic paraplegia.

What condition is associated with KDM5C p.Ser941= (c.2823A>G)?

KDM5C p.Ser941= (c.2823A>G) is associated with Spastic paraplegia (ClinVar).

How common is KDM5C p.Ser941= (c.2823A>G) in the general population?

KDM5C p.Ser941= (c.2823A>G) is rare (popmax 0.184%, amr) (gnomAD).

KDM5C p.Ser941=

c.2823A>G · rs143955805 · VCV211248

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.184%, amr)

Conditions

Spastic paraplegia

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 · T>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.02	GERP -1.8, phastCons 0.78
Overall
CADD	9.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.184% Admixed American · 84/45,710 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.14%

Overall 0.121% 1,463/1,207,911 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.638%	157
Finnishnot grpmax-eligible	0.277%	361
Admixed Americangrpmax	0.184%	544
Remaining individualsnot grpmax-eligible	0.141%	709
European (non-Finnish)	0.113%	886
South Asian	0.0372%	2,686
Middle Eastern	0.0231%	4,333
African / African-American	0.0225%	4,435

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser941=
Coding: c.2823A>G
MANE Select: NM_004187
dbSNP: rs143955805
Type: single nucleotide variant
Location: chrX:53196844 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB

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 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
KDM5C p.Ala1330Thr 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-ser941 (accessed [today's date]).

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