Is DNMT1 p.Ala711Pro (c.2131G>C) pathogenic?

DNMT1 p.Ala711Pro (c.2131G>C) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9813); Absent from gnomAD v4.1.

How common is DNMT1 p.Ala711Pro (c.2131G>C) in the general population?

DNMT1 p.Ala711Pro (c.2131G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT1 p.Ala711Pro (c.2131G>C)?

AlphaMissense predicts likely pathogenic (score 0.9813) — an in-silico prediction, not a clinical call.

DNMT1 p.Ala711Pro

c.2131G>C · VCV3391724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9813 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9813	likely pathogenic
REVEL	0.282	benign-leaning
SaProt	LLR -10.78	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Pangolin	Δ0.21	gain · loss 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 0.88, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 5,615 bp · p 8.2e-17 · regional, not allelic
Overall
CADD	33.0	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 A695P vs ClinVar A711P) — 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.Ala711Pro
Coding: c.2131G>C
MANE Select: NM_001130823
Type: single nucleotide variant
Location: chr19:10151532 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 695 UniProt numbering: an α-helix; the 'required for activity' region; the 'autoinhibitory linker' region

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

Similar variants

DNMT1 p.Ala711= Likely benign ★ 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
DNMT1 c.*253G>A 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-ala711pro (accessed [today's date]).

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