Is CHD3 p.Leu759= (c.2277A>C) pathogenic?

CHD3 p.Leu759= (c.2277A>C) is classified Benign in CHD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-11-07). Common (popmax 10.4%, amr) — too common for a highly-penetrant pathogenic allele.

CHD3 p.Leu759=

Q: How common is CHD3 p.Leu759= (c.2277A>C) in the general population?

CHD3 p.Leu759= (c.2277A>C) is common (popmax 10.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2277A>C · rs11651304 · VCV1252292

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.4%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.87, phastCons 1
Overall
CADD	8.474	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.4% Admixed American · 6,246/59,986 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.1%

Overall 4.41% 71,187/1,614,074 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	12.2%	8
Admixed Americangrpmax	10.4%	10
Finnishnot grpmax-eligible	6.88%	15
South Asian	6.35%	16
Remaining individualsnot grpmax-eligible	4.77%	21
European (non-Finnish)	4.15%	24
Middle Eastern	3.18%	31
Ashkenazi Jewishnot grpmax-eligible	3.03%	33
East Asian	2.18%	46
African / African-American	0.898%	111

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu759=
Coding: c.2277A>C
MANE Select: NM_001005273
dbSNP: rs11651304
Type: single nucleotide variant
Location: chr17:7899136 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 759: the helicase atp-binding domain; 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.Leu759Ile Uncertain significance ★ ⚠ 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
CHD3 p.Arg1169Pro Pathogenic/Likely pathogenic ★★ same type
CHD3 p.Arg1169Trp 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-leu759 (accessed [today's date]).

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