Is KDM5C p.Ser522Phe (c.1565C>T) pathogenic?

KDM5C p.Ser522Phe (c.1565C>T) is classified Likely pathogenic in KDM5C (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-08). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Claes-Jensen type.

What condition is associated with KDM5C p.Ser522Phe (c.1565C>T)?

KDM5C p.Ser522Phe (c.1565C>T) is associated with syndromic X-linked intellectual disability Claes-Jensen type (ClinVar).

How common is KDM5C p.Ser522Phe (c.1565C>T) in the general population?

KDM5C p.Ser522Phe (c.1565C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KDM5C p.Ser522Phe (c.1565C>T)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

KDM5C p.Ser522Phe

c.1565C>T · rs2146915737 · VCV1335879

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Claes-Jensen type

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 3% in KDM5C
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -12.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 10 kb · p 1.4e-30 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KDM5C
Protein: p.Ser522Phe
Coding: c.1565C>T
MANE Select: NM_004187
dbSNP: rs2146915737
Type: single nucleotide variant
Location: chrX:53210694 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB
Residue 522: a binding site; the jmjc domain; a β-strand

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

Disease context

syndromic X-linked intellectual disability Claes-Jensen type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KDM5C p.Arg332Ter Pathogenic ★★ same condition
KDM5C p.Arg599Cys Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg681Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Arg750Trp Likely pathogenic ★★ same condition
KDM5C p.Arg828Ter Pathogenic ★★ same condition
KDM5C p.Arg943Ter Pathogenic/Likely pathogenic ★★ same condition
KDM5C p.Gln1020Ter Pathogenic ★★ same condition
KDM5C p.Gln199Ter Pathogenic ★★ 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-ser522phe (accessed [today's date]).

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