Is CHD2 p.Pro405Leu (c.1214C>T) pathogenic?

CHD2 p.Pro405Leu (c.1214C>T) is classified Benign/Likely benign in CHD2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.072); Rare (popmax 0.106%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Pro405Leu (c.1214C>T)?

CHD2 p.Pro405Leu (c.1214C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy 94 (ClinVar).

How common is CHD2 p.Pro405Leu (c.1214C>T) in the general population?

CHD2 p.Pro405Leu (c.1214C>T) is rare (popmax 0.106%, afr) (gnomAD).

What do computational predictors say about CHD2 p.Pro405Leu (c.1214C>T)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

CHD2 p.Pro405Leu

c.1214C>T · rs370464322 · VCV389781

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.33	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 4.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 9,299 bp · p 6.4e-08 · regional, not allelic
Overall
CADD	23.3	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 0.106% African / African-American · 78/73,898 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0797%

Overall 0.00876% 139/1,585,934 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.106%	947
Admixed American	0.0215%	4,654
Remaining individualsnot grpmax-eligible	0.018%	5,562
South Asian	0.0173%	5,772
Middle Eastern	0.0171%	5,832
East Asian	0.00224%	44,582
European (non-Finnish)	0.0018%	55,489

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.Pro405Leu
Coding: c.1214C>T
MANE Select: NM_001271
dbSNP: rs370464322
Type: single nucleotide variant
Location: chr15:92946053 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 405: the chromo 2 domain; 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

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.Pro405= Likely benign ★ same residue
CHD2 p.Pro405Ala Uncertain significance ★ ⚠ 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

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-pro405leu (accessed [today's date]).

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