Is DNMT1 p.Pro128Ser (c.382C>T) pathogenic?

DNMT1 p.Pro128Ser (c.382C>T) is classified Conflicting classifications of pathogenicity in DNMT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.0579); Ultra-rare (popmax 0.0156%, eas); Associated with Inborn genetic diseases.

How common is DNMT1 p.Pro128Ser (c.382C>T) in the general population?

DNMT1 p.Pro128Ser (c.382C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about DNMT1 p.Pro128Ser (c.382C>T)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

DNMT1 p.Pro128Ser

Q: What condition is associated with DNMT1 p.Pro128Ser (c.382C>T)?

DNMT1 p.Pro128Ser (c.382C>T) is associated with Inborn genetic diseases, autosomal dominant cerebellar ataxia, deafness and narcolepsy, hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

c.382C>T · rs146601335 · VCV539606

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.48	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	GERP -0.76, phastCons 0.14
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	0.843	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,898 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00322% 52/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,414
Admixed American	0.00834%	11,994
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00314%	31,893
African / African-American	0.00134%	74,874

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.Pro128Ser
Coding: c.382C>T
MANE Select: NM_001130823
dbSNP: rs146601335
Type: single nucleotide variant
Location: chr19:10180413 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 128: 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

Disease context

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

Also linked: autosomal dominant cerebellar ataxia, deafness and narcolepsy hereditary sensory neuropathy-deafness-dementia syndrome

Similar variants

DNMT1 p.Pro128= Likely benign ★★ same residue
DNMT1 p.Pro128Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
DNMT1 p.Ala570Val Pathogenic ★★ ⚠ same condition
DNMT1 p.Tyr511Cys Pathogenic/Likely pathogenic ★★ same condition
DNMT1 c.1280+2T>C Uncertain significance ★★ same condition
DNMT1 c.3524-5G>T Uncertain significance ★★ same condition
DNMT1 c.494-4A>G Uncertain significance ★★ same condition
DNMT1 c.*211G>C 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-pro128ser (accessed [today's date]).

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