Is CHD3 p.Pro538Leu (c.1613C>T) pathogenic?

CHD3 p.Pro538Leu (c.1613C>T) is classified Uncertain significance in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-18). AlphaMissense: likely benign (0.0633); Very rare (popmax 0.0022%, sas); Associated with Snijders Blok-Campeau syndrome.

What condition is associated with CHD3 p.Pro538Leu (c.1613C>T)?

CHD3 p.Pro538Leu (c.1613C>T) is associated with Snijders Blok-Campeau syndrome (ClinVar).

How common is CHD3 p.Pro538Leu (c.1613C>T) in the general population?

CHD3 p.Pro538Leu (c.1613C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CHD3 p.Pro538Leu (c.1613C>T)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

CHD3 p.Pro538Leu

c.1613C>T · rs200461939 · VCV1683517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Snijders Blok-Campeau syndrome

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 0.79
Regional constraint	o/e 1.31	unconstrained · MANE · 36 bp · p 0.18 · regional, not allelic
Overall
CADD	16.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000479% 7/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
European (non-Finnish)	0.000424%	235,999

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.Pro538Leu
Coding: c.1613C>T
MANE Select: NM_001005273
dbSNP: rs200461939
Type: single nucleotide variant
Location: chr17:7895448 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 538: 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

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

Similar variants

CHD3 p.Pro538fs Pathogenic ★ same residue
CHD3 p.Pro538Ala Uncertain significance ★ ⚠ same residue
CHD3 p.Pro538Arg 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

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-pro538leu (accessed [today's date]).

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