Is DNMT1 p.Pro306His (c.917C>A) pathogenic?

DNMT1 p.Pro306His (c.917C>A) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-20). AlphaMissense: likely benign (0.1386); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DNMT1 p.Pro306His (c.917C>A)?

DNMT1 p.Pro306His (c.917C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT1 p.Pro306His (c.917C>A) in the general population?

DNMT1 p.Pro306His (c.917C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT1 p.Pro306His (c.917C>A)?

AlphaMissense predicts likely benign (score 0.1386) — an in-silico prediction, not a clinical call.

DNMT1 p.Pro306His

c.917C>A · rs2513847148 · VCV1764333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1386 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1386	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 7.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	22.8	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 P290H vs ClinVar P306H) — 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.Pro306His
Coding: c.917C>A
MANE Select: NM_001130823
dbSNP: rs2513847148
Type: single nucleotide variant
Location: chr19:10163335 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 306: 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

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

Similar variants

DNMT1 p.Pro306Ser Uncertain significance ★★ ⚠ same residue
DNMT1 p.Ala615Val Uncertain significance ★★ ⚠ same condition
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

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-pro306his (accessed [today's date]).

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