Is DNMT1 p.Arg1075Pro (c.3224G>C) pathogenic?

DNMT1 p.Arg1075Pro (c.3224G>C) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-25). AlphaMissense: ambiguous (0.4298); Very rare (popmax 6.84e-05%).

How common is DNMT1 p.Arg1075Pro (c.3224G>C) in the general population?

DNMT1 p.Arg1075Pro (c.3224G>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about DNMT1 p.Arg1075Pro (c.3224G>C)?

AlphaMissense predicts ambiguous (score 0.4298) — an in-silico prediction, not a clinical call.

DNMT1 p.Arg1075Pro

c.3224G>C · VCV4940530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4298	ambiguous
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -7.68	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.92, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 5,517 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	26.7	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 R1059P vs ClinVar R1075P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,444 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.Arg1075Pro
Coding: c.3224G>C
MANE Select: NM_001130823
Type: single nucleotide variant
Location: chr19:10142113 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 1075: an α-helix; the bah 2 domain

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

Similar variants

DNMT1 p.Arg1075His Uncertain significance ★★ ⚠ same residue
DNMT1 p.Arg1075Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
DNMT1 p.Ala570Val Pathogenic ★★ ⚠ same type
DNMT1 p.Tyr511Cys Pathogenic/Likely pathogenic ★★ same type
DNMT1 c.1280+2T>C Uncertain significance ★★ same type
DNMT1 c.3524-5G>T Uncertain significance ★★ same type
DNMT1 c.494-4A>G Uncertain significance ★★ same type
DNMT1 c.*211G>C Uncertain significance ★★ same type

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-arg1075pro (accessed [today's date]).

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