Is CHD3 p.Arg540Cys (c.1618C>T) pathogenic?

CHD3 p.Arg540Cys (c.1618C>T) is classified Likely pathogenic in CHD3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-12). AlphaMissense: likely benign (0.145); Very rare (popmax 0.00223%, eas).

How common is CHD3 p.Arg540Cys (c.1618C>T) in the general population?

CHD3 p.Arg540Cys (c.1618C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHD3 p.Arg540Cys (c.1618C>T)?

AlphaMissense predicts likely benign (score 0.145) — an in-silico prediction, not a clinical call.

CHD3 p.Arg540Cys

c.1618C>T · rs1476775959 · VCV2664669

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.145	likely benign ⚠ discordant with ClinVar
REVEL	0.534	indeterminate
SaProt	LLR -8.04	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 2.7	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.31	unconstrained · MANE · 36 bp · p 0.18 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	0.000254%	393,346

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.Arg540Cys
Coding: c.1618C>T
MANE Select: NM_001005273
dbSNP: rs1476775959
Type: single nucleotide variant
Location: chr17:7895453 (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

Similar variants

CHD3 p.Arg540His Likely benign ★★ same residue
CHD3 p.Arg540Leu Uncertain significance ★ ⚠ same residue
CHD3 p.Arg540fs Pathogenic ★★ same residue
CHD3 c.4073-2A>C Likely pathogenic ★★ same type
CHD3 p.Arg103Ter Pathogenic ★★ same type
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same type
CHD3 p.Arg1121Pro Pathogenic/Likely pathogenic ★★ same type
CHD3 p.Arg1169Gln Pathogenic/Likely pathogenic ★★ same type

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-arg540cys (accessed [today's date]).

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