Is KDM5C p.Pro964Ser (c.2890C>T) pathogenic?

KDM5C p.Pro964Ser (c.2890C>T) is classified Uncertain significance in KDM5C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). AlphaMissense: likely benign (0.1521); Very rare (popmax 0.000558%, nfe).

How common is KDM5C p.Pro964Ser (c.2890C>T) in the general population?

KDM5C p.Pro964Ser (c.2890C>T) is very rare (popmax 0.000558%, nfe) (gnomAD).

What do computational predictors say about KDM5C p.Pro964Ser (c.2890C>T)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

KDM5C p.Pro964Ser

c.2890C>T · rs2519396709 · VCV2446652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000558%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -8.87	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 7.6	GERP -2.3, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,065 bp · p 0.0004 · regional, not allelic
Overall
CADD	23.0	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 0.000558% European (non-Finnish) · 5/895,546 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000546% 6/1,098,093 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,644
European (non-Finnish)grpmax	0.000558%	179,109

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.Pro964Ser
Coding: c.2890C>T
MANE Select: NM_004187
dbSNP: rs2519396709
Type: single nucleotide variant
Location: chrX:53196777 (GRCh38)
Structure: AlphaFold pLDDT 72.50 · 2 PDB

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

Similar variants

KDM5C c.1243-2A>G Pathogenic/Likely pathogenic ★★ same type
KDM5C p.Arg332Ter Pathogenic ★★ same type
KDM5C p.Arg599Cys Pathogenic/Likely pathogenic ★★ same type
KDM5C p.Arg681Ter Pathogenic/Likely pathogenic ★★ same type
KDM5C p.Arg68Ter Pathogenic ★★ same type
KDM5C p.Arg750Trp Likely pathogenic ★★ same type
KDM5C p.Arg778Ter Pathogenic ★★ same type
KDM5C p.Arg828Ter Pathogenic ★★ same type

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-pro964ser (accessed [today's date]).

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