Is CHD3 p.Leu1606Pro (c.4817T>C) pathogenic?

CHD3 p.Leu1606Pro (c.4817T>C) is classified Uncertain significance in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-14). AlphaMissense: likely benign (0.0512); Very rare (popmax 0.00336%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHD3 p.Leu1606Pro (c.4817T>C)?

CHD3 p.Leu1606Pro (c.4817T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHD3 p.Leu1606Pro (c.4817T>C) in the general population?

CHD3 p.Leu1606Pro (c.4817T>C) is very rare (popmax 0.00336%, amr) (gnomAD).

What do computational predictors say about CHD3 p.Leu1606Pro (c.4817T>C)?

AlphaMissense predicts likely benign (score 0.0512) — an in-silico prediction, not a clinical call.

CHD3 p.Leu1606Pro

c.4817T>C · rs771147785 · VCV2333760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0512	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -4.85	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 2.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,113 bp · p 0.44 · regional, not allelic
Overall
CADD	14.55	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 0.00336% Admixed American · 2/59,478 alleles

Filtering AF 0.000885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000445%

Overall 0.000933% 15/1,607,952 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,739
South Asian	0.00333%	30,032
East Asian	0.00223%	44,828
Remaining individualsnot grpmax-eligible	0.00161%	62,216
European (non-Finnish)	0.00068%	147,109

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.Leu1606Pro
Coding: c.4817T>C
MANE Select: NM_001005273
dbSNP: rs771147785
Type: single nucleotide variant
Location: chr17:7907381 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.21
Residue 1606: the 'disordered' region; the 'required for interaction with pcnt' region; a UniProt-annotated variant site (in snibcps)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD3 p.Leu1606Phe Uncertain significance ★ ⚠ same residue
CHD3 p.Arg103Ter Pathogenic ★★ same condition
CHD3 p.Arg1078Gln Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Arg966Trp Pathogenic ★★ same condition
CHD3 p.Arg985Trp Pathogenic/Likely pathogenic ★★ same condition
CHD3 p.Pro1918= Likely pathogenic ★★ same condition
CHD3 p.Arg1266Trp Uncertain significance ★★ ⚠ same condition
CHD3 p.Arg1377Cys Uncertain significance ★★ ⚠ 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-leu1606pro (accessed [today's date]).

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