Is DNMT1 p.Val606Phe (c.1816G>T) pathogenic?

DNMT1 p.Val606Phe (c.1816G>T) is classified Likely pathogenic in DNMT1 (ClinVar, Single submitter, 3 submitters; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.7952); Absent from gnomAD v4.1; Associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy.

What condition is associated with DNMT1 p.Val606Phe (c.1816G>T)?

DNMT1 p.Val606Phe (c.1816G>T) is associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy, hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Val606Phe (c.1816G>T) in the general population?

DNMT1 p.Val606Phe (c.1816G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT1 p.Val606Phe (c.1816G>T)?

AlphaMissense predicts likely pathogenic (score 0.7952) — an in-silico prediction, not a clinical call.

DNMT1 p.Val606Phe

Q: How is Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.1816G>T · rs397509391 · VCV50919

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant cerebellar ataxia, deafness and narcolepsy

Computational evidence

Protein change
AlphaMissense	0.7952	likely pathogenic ✓ concordant with ClinVar
REVEL	0.495	indeterminate
SaProt	LLR -13.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 5,615 bp · p 8.2e-17 · regional, not allelic
Overall
CADD	26.0	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 V590F vs ClinVar V606F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT1
Protein: p.Val606Phe
Coding: c.1816G>T
MANE Select: NM_001130823
dbSNP: rs397509391
Type: single nucleotide variant
Location: chr19:10154602 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 606: the 'interaction with the prc2/eed-ezh2 complex' region

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

Disease context

autosomal dominant cerebellar ataxia, deafness and narcolepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary sensory neuropathy-deafness-dementia syndrome

For Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: 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-val606phe (accessed [today's date]).

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