Is CHD2 p.Arg225Lys (c.674G>A) pathogenic?

CHD2 p.Arg225Lys (c.674G>A) is classified Uncertain significance in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-29). AlphaMissense: likely benign (0.2002); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHD2 p.Arg225Lys (c.674G>A)?

CHD2 p.Arg225Lys (c.674G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CHD2 p.Arg225Lys (c.674G>A) in the general population?

CHD2 p.Arg225Lys (c.674G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CHD2 p.Arg225Lys (c.674G>A)?

AlphaMissense predicts likely benign (score 0.2002) — an in-silico prediction, not a clinical call.

CHD2 p.Arg225Lys

c.674G>A · rs1304008714 · VCV589966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2002	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -7.87	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 12	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	25.5	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

Grpmax group 0.00267% African / African-American · 2/75,034 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,490 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,517
Admixed American	0.00167%	59,986

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.Arg225Lys
Coding: c.674G>A
MANE Select: NM_001271
dbSNP: rs1304008714
Type: single nucleotide variant
Location: chr15:92939700 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 225: 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

Similar variants

CHD2 p.Arg225Ile Uncertain significance ★ ⚠ same residue
CHD2 c.443+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Ala879Val Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Arg1152Trp Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Arg1637Ter Pathogenic ★★ same condition
CHD2 p.Arg1679Ter Pathogenic ★★ same condition
CHD2 p.Arg699Trp Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Arg804Ter 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-arg225lys (accessed [today's date]).

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