Is DNMT1 p.Arg1223= (c.3669C>T) pathogenic?

DNMT1 p.Arg1223= (c.3669C>T) is classified Benign/Likely benign in DNMT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-08). Ultra-rare (popmax 0.0221%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNMT1 p.Arg1223= (c.3669C>T)?

DNMT1 p.Arg1223= (c.3669C>T) is associated with Inborn genetic diseases, hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Arg1223= (c.3669C>T) in the general population?

DNMT1 p.Arg1223= (c.3669C>T) is ultra-rare (popmax 0.0221%, nfe) (gnomAD).

DNMT1 p.Arg1223=

c.3669C>T · rs147755768 · VCV707638

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.2
Overall
CADD	1.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0221% European (non-Finnish) · 261/1,180,030 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0169% 272/1,613,982 alleles · ultra-rare exomes 259/1,461,654 · genomes 13/152,328 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0221%	4,521
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.004%	25,016
South Asian	0.0022%	45,544

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: DNMT1
Protein: p.Arg1223=
Coding: c.3669C>T
MANE Select: NM_001130823
dbSNP: rs147755768
Type: single nucleotide variant
Location: chr19:10140183 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 1223: the sam-dependent mtase c5-type domain; the 'interaction with the prc2/eed-ezh2 complex' region

Full DNMT1 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

Also linked: hereditary sensory neuropathy-deafness-dementia syndrome

Similar variants

DNMT1 p.Arg1223Cys Uncertain significance ★★ ⚠ same residue
DNMT1 p.Arg1223His Conflicting classifications of pathogenicity ★ ⚠ same residue
DNMT1 p.Ala570Val Pathogenic ★★ ⚠ same condition
DNMT1 p.Tyr511Cys Pathogenic/Likely pathogenic ★★ same condition
DNMT1 c.1280+2T>C Uncertain significance ★★ same condition
DNMT1 c.3524-5G>T Uncertain significance ★★ same condition
DNMT1 c.494-4A>G Uncertain significance ★★ same condition
DNMT1 c.*211G>C 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/dnmt1-p-arg1223 (accessed [today's date]).

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