Is DNMT1 p.Cys683= (c.2049T>C) pathogenic?

DNMT1 p.Cys683= (c.2049T>C) is classified Likely benign in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). Very rare (popmax 0.00134%, afr); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Cys683= (c.2049T>C)?

DNMT1 p.Cys683= (c.2049T>C) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Cys683= (c.2049T>C) in the general population?

DNMT1 p.Cys683= (c.2049T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

DNMT1 p.Cys683=

Q: How is Hereditary sensory neuropathy-deafness-dementia syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2049T>C · rs1035603642 · VCV1128658

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

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 1.7	GERP -4.2, phastCons 1
Overall
CADD	8.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,890 alleles

Overall 6.2e-05% 1/1,613,986 alleles · very rare exomes 0/1,461,868 · genomes 1/152,118 · joint denominator

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.Cys683=
Coding: c.2049T>C
MANE Select: NM_001130823
dbSNP: rs1035603642
Type: single nucleotide variant
Location: chr19:10151818 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 683: the 'required for activity' region

Full DNMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary sensory neuropathy-deafness-dementia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory neuropathy-deafness-dementia syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

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
DNMT1 c.*253G>A Uncertain significance ★★ same condition
DNMT1 p.Ala1053Thr 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-cys683 (accessed [today's date]).

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