Is DNMT1 p.Val286Ala (c.857T>C) pathogenic?

DNMT1 p.Val286Ala (c.857T>C) is classified Uncertain significance in DNMT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-23). AlphaMissense: likely benign (0.0629); Very rare (popmax 0.00161%, nfe); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Val286Ala (c.857T>C)?

DNMT1 p.Val286Ala (c.857T>C) is associated with hereditary sensory neuropathy-deafness-dementia syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy (ClinVar).

How common is DNMT1 p.Val286Ala (c.857T>C) in the general population?

DNMT1 p.Val286Ala (c.857T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about DNMT1 p.Val286Ala (c.857T>C)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

DNMT1 p.Val286Ala

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.857T>C · rs766504703 · VCV573027

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	0.691	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V270A vs ClinVar V286A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,042 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,614,008 alleles · very rare exomes 17/1,461,872 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)grpmax	0.00161%	62,108

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val286Ala
Coding: c.857T>C
MANE Select: NM_001130823
dbSNP: rs766504703
Type: single nucleotide variant
Location: chr19:10166632 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 270 UniProt numbering: the 'interaction with the prc2/eed-ezh2 complex' region; the 'disordered' 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

Also linked: autosomal dominant cerebellar ataxia, deafness and narcolepsy

For Hereditary sensory neuropathy-deafness-dementia syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DNMT1 p.Val286Met Likely benign ★★ same residue
DNMT1 p.Val286Leu 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

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-val286ala (accessed [today's date]).

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