Is CHD3 p.Arg540His (c.1619G>A) pathogenic?

CHD3 p.Arg540His (c.1619G>A) is classified Likely benign in CHD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-01). AlphaMissense: likely benign (0.101); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHD3 p.Arg540His (c.1619G>A)?

CHD3 p.Arg540His (c.1619G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CHD3 p.Arg540His (c.1619G>A) in the general population?

CHD3 p.Arg540His (c.1619G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CHD3 p.Arg540His (c.1619G>A)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

CHD3 p.Arg540His

c.1619G>A · rs754854794 · VCV2380902

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -6.93	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 36 bp · p 0.18 · regional, not allelic
Overall
CADD	25.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00335% 54/1,613,908 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.015%	6,665
African / African-American	0.012%	8,317
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
European (non-Finnish)	0.00254%	39,334
South Asian	0.0022%	45,545
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg540His
Coding: c.1619G>A
MANE Select: NM_001005273
dbSNP: rs754854794
Type: single nucleotide variant
Location: chr17:7895454 (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.Arg540fs Pathogenic ★★ same residue
CHD3 p.Arg540Leu Uncertain significance ★ ⚠ same residue
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
CHD3 p.Arg985Trp Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Pro1918= 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/chd3-p-arg540his (accessed [today's date]).

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