Is KDM5C p.Pro218Ser (c.652C>T) pathogenic?

KDM5C p.Pro218Ser (c.652C>T) is classified Conflicting classifications of pathogenicity in KDM5C (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-16). AlphaMissense: likely benign (0.2469); Very rare (popmax 0.00112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KDM5C p.Pro218Ser (c.652C>T)?

KDM5C p.Pro218Ser (c.652C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KDM5C p.Pro218Ser (c.652C>T) in the general population?

KDM5C p.Pro218Ser (c.652C>T) is very rare (popmax 0.00112%, nfe) (gnomAD).

What do computational predictors say about KDM5C p.Pro218Ser (c.652C>T)?

AlphaMissense predicts likely benign (score 0.2469) — an in-silico prediction, not a clinical call.

KDM5C p.Pro218Ser

c.652C>T · rs782076366 · VCV1672626

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2469	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 2,177 bp · p 6.7e-09 · regional, not allelic
Overall
CADD	22.2	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 0.00112% European (non-Finnish) · 10/893,027 alleles

Filtering AF 0.000566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000413%

Overall 0.000912% 11/1,205,873 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00211%	47,436
European (non-Finnish)grpmax	0.00112%	89,302

Remaining individuals 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.Pro218Ser
Coding: c.652C>T
MANE Select: NM_004187
dbSNP: rs782076366
Type: single nucleotide variant
Location: chrX:53217148 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 218: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Arg68Ter Pathogenic ★★ same condition
KDM5C p.Gln1020Ter Pathogenic ★★ same condition
KDM5C p.Gln859Ter Pathogenic ★★ same condition
KDM5C p.Glu698Lys Likely pathogenic ★★ same condition
KDM5C p.Arg367Trp Uncertain significance ★★ ⚠ same condition
KDM5C p.Arg909Trp Uncertain significance ★★ ⚠ same condition
KDM5C p.Gln859Lys Uncertain significance ★★ ⚠ same condition
KDM5C p.Glu1276Lys 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-pro218ser (accessed [today's date]).

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