Is DNMT1 p.Pro129Thr (c.385C>A) pathogenic?

DNMT1 p.Pro129Thr (c.385C>A) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-11). AlphaMissense: likely benign (0.0615); Very rare (popmax 8.47e-05%, nfe).

How common is DNMT1 p.Pro129Thr (c.385C>A) in the general population?

DNMT1 p.Pro129Thr (c.385C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DNMT1 p.Pro129Thr (c.385C>A)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

DNMT1 p.Pro129Thr

c.385C>A · rs1085307715 · VCV426621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.86	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 1.4	GERP 0.92, phastCons 0.81
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	0.525	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 6.2e-05% 1/1,614,032 alleles · very rare exomes 1/1,461,796 · genomes 0/152,236 · joint denominator

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.Pro129Thr
Coding: c.385C>A
MANE Select: NM_001130823
dbSNP: rs1085307715
Type: single nucleotide variant
Location: chr19:10180410 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 129: the 'interaction with the prc2/eed-ezh2 complex' region; the 'interaction with dnmt3a' region; the 'disordered' region

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

Similar variants

DNMT1 p.Pro129= Benign/Likely benign ★★ same residue
DNMT1 p.Pro129Ala Uncertain significance ★ ⚠ same residue
DNMT1 p.Pro129Arg Uncertain significance ★ ⚠ same residue
DNMT1 p.Pro129Leu Uncertain significance ★ ⚠ 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

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-pro129thr (accessed [today's date]).

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