Is DNMT1 p.Ala615Val (c.1844C>T) pathogenic?

DNMT1 p.Ala615Val (c.1844C>T) is classified Uncertain significance in DNMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with DNMT1 p.Ala615Val (c.1844C>T)?

DNMT1 p.Ala615Val (c.1844C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT1 p.Ala615Val (c.1844C>T) in the general population?

DNMT1 p.Ala615Val (c.1844C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DNMT1 p.Ala615Val (c.1844C>T)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

DNMT1 p.Ala615Val

c.1844C>T · rs753235229 · VCV1780269

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -6.87	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 2.6	GERP -0.8, phastCons 0.48
Regional constraint	o/e 0.56	unconstrained · MANE · 5,615 bp · p 8.2e-17 · regional, not allelic
Overall
CADD	8.876	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 A599V vs ClinVar A615V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,036 alleles · very rare exomes 4/1,461,894 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000339%	295,007

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.Ala615Val
Coding: c.1844C>T
MANE Select: NM_001130823
dbSNP: rs753235229
Type: single nucleotide variant
Location: chr19:10154468 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 599 UniProt numbering: 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

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

Similar variants

DNMT1 p.Ala615= Benign/Likely benign ★★ same residue
DNMT1 p.Arg1011Gln Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg1120His Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg114Lys Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg1226Gln Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg1254Cys Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg1442Gln Uncertain significance ★★ ⚠ same condition
DNMT1 p.Arg149Ser 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-ala615val (accessed [today's date]).

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