Is DNMT1 p.Lys336= (c.1008G>A) pathogenic?

DNMT1 p.Lys336= (c.1008G>A) is classified Uncertain significance in DNMT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-02). Very rare (popmax 0.000425%, nfe); Associated with Inborn genetic diseases.

How common is DNMT1 p.Lys336= (c.1008G>A) in the general population?

DNMT1 p.Lys336= (c.1008G>A) is very rare (popmax 0.000425%, nfe) (gnomAD).

DNMT1 p.Lys336=

Q: What condition is associated with DNMT1 p.Lys336= (c.1008G>A)?

DNMT1 p.Lys336= (c.1008G>A) is associated with Inborn genetic diseases, autosomal dominant cerebellar ataxia, deafness and narcolepsy, hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

c.1008G>A · rs750048459 · VCV1061265

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.85	donor gain · deltas
Pangolin	Δ0.77	gain · loss 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 6.1, phastCons 1
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,176,358 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000311% 5/1,608,246 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.Lys336=
Coding: c.1008G>A
MANE Select: NM_001130823
dbSNP: rs750048459
Type: single nucleotide variant
Location: chr19:10162667 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 336: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant cerebellar ataxia, deafness and narcolepsy hereditary sensory neuropathy-deafness-dementia syndrome

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-lys336 (accessed [today's date]).

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