Is CHD2 p.Lys1245fs (c.3735del) pathogenic?

CHD2 p.Lys1245fs (c.3735del) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-22). Ultra-rare (popmax 0.055%, amr); Associated with History of neurodevelopmental disorder.

What condition is associated with CHD2 p.Lys1245fs (c.3735del)?

CHD2 p.Lys1245fs (c.3735del) is associated with History of neurodevelopmental disorder, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Lys1245fs (c.3735del) in the general population?

CHD2 p.Lys1245fs (c.3735del) is ultra-rare (popmax 0.055%, amr) (gnomAD).

CHD2 p.Lys1245fs

c.3735del · rs752940775 · VCV425077

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Conditions

History of neurodevelopmental disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 29 of 39
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Admixed American · 27/49,114 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.00793% 116/1,462,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,819
South Asian	0.0221%	4,530
Remaining individualsnot grpmax-eligible	0.0179%	5,575
Ashkenazi Jewishnot grpmax-eligible	0.0153%	6,516
Finnishnot grpmax-eligible	0.00871%	11,485
African / African-American	0.0087%	11,489
European (non-Finnish)	0.00426%	23,496
East Asian	0.00246%	40,584

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.Lys1245fs
Coding: c.3735del
MANE Select: NM_001271
dbSNP: rs752940775
Type: Deletion
Location: chr15:92997086 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1245: a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance)

Full CHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

History of neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy 94

Similar variants

CHD2 p.Lys1245Gln Uncertain significance ★ ⚠ same residue
CHD2 p.Glu1412fs Pathogenic ★★ same condition
CHD2 p.Lys1393fs Pathogenic ★★ same condition
CHD2 p.Lys174_Val175insTer Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Pro399fs Pathogenic ★★ same condition
CHD2 c.1199-12del Benign/Likely benign ★★ same condition
CHD2 c.381+12del Likely benign ★★ same condition
CHD2 p.Lys1411del Benign/Likely benign ★★ 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-lys1245fs (accessed [today's date]).

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