Is CHD3 p.Arg540fs (c.1618dup) pathogenic?

CHD3 p.Arg540fs (c.1618dup) is classified Pathogenic in CHD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-04). Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD3 p.Arg540fs (c.1618dup)?

CHD3 p.Arg540fs (c.1618dup) is associated with Inborn genetic diseases (ClinVar).

How common is CHD3 p.Arg540fs (c.1618dup) in the general population?

CHD3 p.Arg540fs (c.1618dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

CHD3 p.Arg540fs

c.1618dup · rs747299117 · VCV1803610

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Inborn genetic diseases

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 LoF-intolerant gene
NMD	predicted	premature termination codon in exon 10 of 40
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.51	GERP -1.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,740 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,728 alleles · very rare exomes 2/1,461,522 · genomes 0/151,206 · joint denominator

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: CHD3
Protein: p.Arg540fs
Coding: c.1618dup
MANE Select: NM_001005273
dbSNP: rs747299117
Type: Duplication
Location: chr17:7895446 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 540: the chromo 1 domain; the 'disordered' region; a UniProt-annotated variant site (in snibcps)

Full CHD3 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

CHD3 p.Arg540His Likely benign ★★ same residue
CHD3 p.Met1220fs Pathogenic ★ same condition
CHD3 p.Arg540Leu Uncertain significance ★ ⚠ same residue
CHD3 p.Glu1652fs Uncertain significance ★ same condition
CHD3 p.Arg540Cys Likely pathogenic ⚠ same residue
CHD3 p.Arg103Ter Pathogenic ★★ same condition
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg966Trp 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/chd3-p-arg540fs (accessed [today's date]).

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