Is CHD3 p.Arg1377His (c.4130G>A) pathogenic?

CHD3 p.Arg1377His (c.4130G>A) is classified Uncertain significance in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-25). AlphaMissense: likely pathogenic (0.71); Very rare (popmax 0.005%, amr); Associated with Snijders Blok-Campeau syndrome.

What condition is associated with CHD3 p.Arg1377His (c.4130G>A)?

CHD3 p.Arg1377His (c.4130G>A) is associated with Snijders Blok-Campeau syndrome (ClinVar).

How common is CHD3 p.Arg1377His (c.4130G>A) in the general population?

CHD3 p.Arg1377His (c.4130G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CHD3 p.Arg1377His (c.4130G>A)?

AlphaMissense predicts likely pathogenic (score 0.71) — an in-silico prediction, not a clinical call.

CHD3 p.Arg1377His

c.4130G>A · VCV4846989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.71 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Snijders Blok-Campeau syndrome

Computational evidence

Protein change
AlphaMissense	0.71	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 3,550 bp · p 4.9e-38 · regional, not allelic
Overall
CADD	34.0	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 0.005% Admixed American · 3/60,026 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000547% 8/1,461,698 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,009
African / African-American	0.00267%	37,517
European (non-Finnish)	0.000254%	393,286

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.Arg1377His
Coding: c.4130G>A
MANE Select: NM_001005273
Type: single nucleotide variant
Location: chr17:7905157 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 1377: 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

Snijders Blok-Campeau syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD3 p.Arg1377Cys Uncertain significance ★★ ⚠ same residue
CHD3 c.4073-2A>C Likely pathogenic ★★ same condition
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg1121Pro Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg1169Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg1169Pro Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg1169Trp Pathogenic ★★ same condition
CHD3 p.Arg1172Gln Pathogenic/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-arg1377his (accessed [today's date]).

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