Is CHD2 p.Lys1389Gln (c.4165A>C) pathogenic?

CHD2 p.Lys1389Gln (c.4165A>C) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.2335); Very rare (popmax 0.00565%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Lys1389Gln (c.4165A>C)?

CHD2 p.Lys1389Gln (c.4165A>C) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Lys1389Gln (c.4165A>C) in the general population?

CHD2 p.Lys1389Gln (c.4165A>C) is very rare (popmax 0.00565%, amr) (gnomAD).

What do computational predictors say about CHD2 p.Lys1389Gln (c.4165A>C)?

AlphaMissense predicts likely benign (score 0.2335) — an in-silico prediction, not a clinical call.

CHD2 p.Lys1389Gln

c.4165A>C · rs762950368 · VCV474390

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00565%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2335	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -8.36	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 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,067 bp · p 0.73 · regional, not allelic
Overall
CADD	23.9	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 0.00565% Admixed American · 3/53,132 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000815%

Overall 0.000693% 11/1,586,574 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0114%	8,762
Admixed Americangrpmax	0.00565%	17,711
European (non-Finnish)	8.54e-05%	1,170,430

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: CHD2
Protein: p.Lys1389Gln
Coding: c.4165A>C
MANE Select: NM_001271
dbSNP: rs762950368
Type: single nucleotide variant
Location: chr15:93002204 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1389: a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance); the 'disordered' region

Full CHD2 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

Also linked: developmental and epileptic encephalopathy 94

Similar variants

CHD2 p.Lys1389Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD2 c.1153+1G>C Pathogenic ★★ same condition
CHD2 c.1809+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD2 c.294+1G>T Likely pathogenic ★★ same condition
CHD2 c.443+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD2 c.693-1G>A Likely pathogenic ★★ same condition
CHD2 p.Ala879Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
CHD2 p.Arg1072Ter 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/chd2-p-lys1389gln (accessed [today's date]).

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