Is DNMT1 p.Asp332= (c.996C>T) pathogenic?

DNMT1 p.Asp332= (c.996C>T) is classified Benign in DNMT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). Common (popmax 5.92%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Asp332= (c.996C>T)?

DNMT1 p.Asp332= (c.996C>T) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

DNMT1 p.Asp332=

Q: How common is DNMT1 p.Asp332= (c.996C>T) in the general population?

DNMT1 p.Asp332= (c.996C>T) is common (popmax 5.92%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.996C>T · rs16999358 · VCV327917

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 5.92%, eas) — too common for a highly-penetrant pathogenic allele

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 -0.41	GERP -4.9, phastCons 0.002
Overall
CADD	8.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.92% East Asian · 2,653/44,820 alleles

Filtering AF 5.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.66%

Overall 0.24% 3,869/1,611,458 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	5.92%	17
Finnishnot grpmax-eligible	0.667%	150
Ashkenazi Jewishnot grpmax-eligible	0.591%	169
Remaining individualsnot grpmax-eligible	0.376%	266
Middle Eastern	0.0497%	2,013
South Asian	0.0385%	2,600
European (non-Finnish)	0.0276%	3,617
Admixed American	0.0217%	4,602
African / African-American	0.0107%	9,317

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.Asp332=
Coding: c.996C>T
MANE Select: NM_001130823
dbSNP: rs16999358
Type: single nucleotide variant
Location: chr19:10162679 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 332: the 'interaction with the prc2/eed-ezh2 complex' region; the 'disordered' region; 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-asp332 (accessed [today's date]).

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