Is DNMT1 p.Val286Met (c.856G>A) pathogenic?

DNMT1 p.Val286Met (c.856G>A) is classified Likely benign in DNMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0227%, afr); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Val286Met (c.856G>A)?

DNMT1 p.Val286Met (c.856G>A) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Val286Met (c.856G>A) in the general population?

DNMT1 p.Val286Met (c.856G>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about DNMT1 p.Val286Met (c.856G>A)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

DNMT1 p.Val286Met

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.856G>A · rs368960099 · VCV546126

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.46	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 -1.9	GERP -1.7
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	0.723	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 V270M vs ClinVar V286M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,942 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00167% 27/1,614,096 alleles · ultra-rare exomes 13/1,461,860 · genomes 14/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,408
Remaining individualsnot grpmax-eligible	0.0032%	31,244
East Asian	0.00223%	44,898
European (non-Finnish)	0.000593%	168,577

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.Val286Met
Coding: c.856G>A
MANE Select: NM_001130823
dbSNP: rs368960099
Type: single nucleotide variant
Location: chr19:10166633 (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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DNMT1 p.Val286Ala Uncertain significance ★★ ⚠ 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-val286met (accessed [today's date]).

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