Is CHD3 p.Arg281Cys (c.841C>T) pathogenic?

CHD3 p.Arg281Cys (c.841C>T) is classified Likely benign in CHD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2678); Ultra-rare (popmax 0.0176%, sas).

How common is CHD3 p.Arg281Cys (c.841C>T) in the general population?

CHD3 p.Arg281Cys (c.841C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about CHD3 p.Arg281Cys (c.841C>T)?

AlphaMissense predicts likely benign (score 0.2678) — an in-silico prediction, not a clinical call.

CHD3 p.Arg281Cys

c.841C>T · rs201932618 · VCV2647425

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2678	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 829 bp · p 0.013 · regional, not allelic
Overall
CADD	27.5	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 0.0176% South Asian · 16/91,068 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00867% 140/1,613,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,692
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00958%	10,443
Admixed American	0.00333%	29,994
East Asian	0.00223%	44,880

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.Arg281Cys
Coding: c.841C>T
MANE Select: NM_001005273
dbSNP: rs201932618
Type: single nucleotide variant
Location: chr17:7893852 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 281: the 'disordered' region

Full CHD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD3 p.Arg281His Likely benign ★★ ⚠ 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-arg281cys (accessed [today's date]).

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