Is CHD2 p.Pro1749Arg (c.5246C>G) pathogenic?

CHD2 p.Pro1749Arg (c.5246C>G) is classified Uncertain significance in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-01). AlphaMissense: ambiguous (0.4592); Very rare (popmax 0.000169%, nfe).

How common is CHD2 p.Pro1749Arg (c.5246C>G) in the general population?

CHD2 p.Pro1749Arg (c.5246C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CHD2 p.Pro1749Arg (c.5246C>G)?

AlphaMissense predicts ambiguous (score 0.4592) — an in-silico prediction, not a clinical call.

CHD2 p.Pro1749Arg

c.5246C>G · rs370256848 · VCV2428929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4592	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -7.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 9,988 bp · p 0.77 · regional, not allelic
Overall
CADD	26.0	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 0.000169% European (non-Finnish) · 2/1,180,046 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,078 alleles · very rare exomes 2/1,461,890 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000169%	590,023

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CHD2
Protein: p.Pro1749Arg
Coding: c.5246C>G
MANE Select: NM_001271
dbSNP: rs370256848
Type: single nucleotide variant
Location: chr15:93024464 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 1749: the 'disordered' region; a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance)

Full CHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD2 p.Pro1749= Likely benign ★★ same residue
CHD2 p.Pro1749Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHD2 p.Pro1749Thr Uncertain significance ★ ⚠ same residue
CHD2 c.1153+1G>C Pathogenic ★★ same type
CHD2 c.1809+1G>A Pathogenic/Likely pathogenic ★★ same type
CHD2 c.294+1G>T Likely pathogenic ★★ same type
CHD2 c.443+1G>A Pathogenic/Likely pathogenic ★★ same type
CHD2 c.693-1G>A Likely 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/chd2-p-pro1749arg (accessed [today's date]).

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