Is KDM5C p.Ser331Cys (c.992C>G) pathogenic?

KDM5C p.Ser331Cys (c.992C>G) is classified Uncertain significance in KDM5C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-11). AlphaMissense: likely benign (0.1); Absent from gnomAD v4.1.

How common is KDM5C p.Ser331Cys (c.992C>G) in the general population?

KDM5C p.Ser331Cys (c.992C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KDM5C p.Ser331Cys (c.992C>G)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

KDM5C p.Ser331Cys

c.992C>G · VCV4685061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -8.11	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 7.4	GERP 0.21, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 4,253 bp · p 4.1e-05 · regional, not allelic
Overall
CADD	23.5	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

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.Ser331Cys
Coding: c.992C>G
MANE Select: NM_004187
Type: single nucleotide variant
Location: chrX:53214819 (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-ser331cys (accessed [today's date]).

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