Is DNMT1 p.Leu402= (c.1206G>C) pathogenic?

DNMT1 p.Leu402= (c.1206G>C) is classified Benign/Likely benign in DNMT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). Rare (popmax 0.565%, afr); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Leu402= (c.1206G>C)?

DNMT1 p.Leu402= (c.1206G>C) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Leu402= (c.1206G>C) in the general population?

DNMT1 p.Leu402= (c.1206G>C) is rare (popmax 0.565%, afr) (gnomAD).

DNMT1 p.Leu402=

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.1206G>C · rs147235870 · VCV383726

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.565%, 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 0.69	GERP 1.8, phastCons 1
Overall
CADD	8.168	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.565% African / African-American · 424/75,060 alleles

Filtering AF 0.521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.503%

Overall 0.0281% 453/1,614,232 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.565%	177
Remaining individualsnot grpmax-eligible	0.0256%	3,907
Admixed American	0.0183%	5,456
Middle Eastern	0.0165%	6,062
European (non-Finnish)	8.47e-05%	1,180,040

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.Leu402=
Coding: c.1206G>C
MANE Select: NM_001130823
dbSNP: rs147235870
Type: single nucleotide variant
Location: chr19:10159732 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 402: the 'interaction with the prc2/eed-ezh2 complex' region; the rfts domain; the 'homodimerization' 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-leu402 (accessed [today's date]).

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