Is CHD3 p.Pro539Arg (c.1616C>G) pathogenic?

CHD3 p.Pro539Arg (c.1616C>G) is classified Likely benign in CHD3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-15). AlphaMissense: likely benign (0.1417); Rare (popmax 0.256%, eas); Associated with CHD3-related disorder.

What condition is associated with CHD3 p.Pro539Arg (c.1616C>G)?

CHD3 p.Pro539Arg (c.1616C>G) is associated with CHD3-related disorder (ClinVar).

How common is CHD3 p.Pro539Arg (c.1616C>G) in the general population?

CHD3 p.Pro539Arg (c.1616C>G) is rare (popmax 0.256%, eas) (gnomAD).

What do computational predictors say about CHD3 p.Pro539Arg (c.1616C>G)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

CHD3 p.Pro539Arg

c.1616C>G · rs201739166 · VCV3047878

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.256%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CHD3-related disorder

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -8.78	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 4.9	GERP 0.9, phastCons 0.59
Regional constraint	o/e 1.31	unconstrained · MANE · 36 bp · p 0.18 · regional, not allelic
Overall
CADD	21.5	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 0.256% East Asian · 115/44,866 alleles

Filtering AF 0.218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.00929% 150/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.256%	390
Admixed American	0.02%	5,003
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.00133%	75,030
European (non-Finnish)	0.000932%	107,274

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.Pro539Arg
Coding: c.1616C>G
MANE Select: NM_001005273
dbSNP: rs201739166
Type: single nucleotide variant
Location: chr17:7895451 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 539: 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

CHD3-related disorder

Similar variants

CHD3 p.Arg1172Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg1342Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg985Gln Pathogenic ★★ same condition
CHD3 p.Arg1491His Uncertain significance ★★ ⚠ same condition
CHD3 p.Arg684Ter Pathogenic ★ same condition
CHD3 p.Glu1653Ter Likely pathogenic ★ same condition
CHD3 p.Met1085Ile Likely pathogenic ★ same condition
CHD3 p.Ala1289Thr Conflicting classifications of pathogenicity ★ ⚠ 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-pro539arg (accessed [today's date]).

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