Is CHD2 p.Pro1353Leu (c.4058C>T) pathogenic?

CHD2 p.Pro1353Leu (c.4058C>T) is classified Conflicting classifications of pathogenicity in CHD2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.0805); Ultra-rare (popmax 0.0176%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Pro1353Leu (c.4058C>T)?

CHD2 p.Pro1353Leu (c.4058C>T) is associated with Inborn genetic diseases, self-limited epilepsy with centrotemporal spikes, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Pro1353Leu (c.4058C>T) in the general population?

CHD2 p.Pro1353Leu (c.4058C>T) is ultra-rare (popmax 0.0176%, nfe) (gnomAD).

What do computational predictors say about CHD2 p.Pro1353Leu (c.4058C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

CHD2 p.Pro1353Leu

c.4058C>T · rs755088564 · VCV425079

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -6.28	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,067 bp · p 0.73 · regional, not allelic
Overall
CADD	26.3	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 0.0176% European (non-Finnish) · 208/1,179,718 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.0136% 220/1,613,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0176%	5,672
Remaining individualsnot grpmax-eligible	0.00961%	10,409
African / African-American	0.00534%	18,723
South Asian	0.0022%	45,516

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.Pro1353Leu
Coding: c.4058C>T
MANE Select: NM_001271
dbSNP: rs755088564
Type: single nucleotide variant
Location: chr15:93000561 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1353: 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: self-limited epilepsy with centrotemporal spikes developmental and epileptic encephalopathy 94 complex neurodevelopmental disorder

Similar variants

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
CHD2 p.Arg1137Ter Pathogenic/Likely 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-pro1353leu (accessed [today's date]).

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