Is DNMT1 p.Asp1114Val (c.3341A>T) pathogenic?

DNMT1 p.Asp1114Val (c.3341A>T) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-27). AlphaMissense: likely pathogenic (0.8588); Very rare (popmax 0.00223%, eas); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Asp1114Val (c.3341A>T)?

DNMT1 p.Asp1114Val (c.3341A>T) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Asp1114Val (c.3341A>T) in the general population?

DNMT1 p.Asp1114Val (c.3341A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DNMT1 p.Asp1114Val (c.3341A>T)?

AlphaMissense predicts likely pathogenic (score 0.8588) — an in-silico prediction, not a clinical call.

DNMT1 p.Asp1114Val

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.3341A>T · rs2513783153 · VCV2731041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
AlphaMissense	0.8588	likely pathogenic
REVEL	0.768	pathogenic-leaning
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 5,517 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D1098V vs ClinVar D1114V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.84e-05% 1/1,461,724 alleles · very rare

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.Asp1114Val
Coding: c.3341A>T
MANE Select: NM_001130823
dbSNP: rs2513783153
Type: single nucleotide variant
Location: chr19:10141158 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 1114: the 'disordered' region; the '6 x 2 aa tandem repeats of k-g' 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.Asp1114Gly Uncertain significance ★ ⚠ 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
DNMT1 c.*253G>A 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-asp1114val (accessed [today's date]).

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