Is DNMT1 p.Pro348Leu (c.1043C>T) pathogenic?

DNMT1 p.Pro348Leu (c.1043C>T) is classified Conflicting classifications of pathogenicity in DNMT1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-01). AlphaMissense: likely benign (0.066); Ultra-rare (popmax 0.0156%, eas); Associated with Inborn genetic diseases.

What condition is associated with DNMT1 p.Pro348Leu (c.1043C>T)?

DNMT1 p.Pro348Leu (c.1043C>T) is associated with Inborn genetic diseases, hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Pro348Leu (c.1043C>T) in the general population?

DNMT1 p.Pro348Leu (c.1043C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about DNMT1 p.Pro348Leu (c.1043C>T)?

AlphaMissense predicts likely benign (score 0.066) — an in-silico prediction, not a clinical call.

DNMT1 p.Pro348Leu

c.1043C>T · rs370592431 · VCV644560

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.066 · 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	0.066	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -8.21	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 0.27	GERP 4.1, phastCons 0.97
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	14.36	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 P332L vs ClinVar P348L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,892 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00211% 34/1,614,126 alleles · ultra-rare exomes 23/1,461,802 · genomes 11/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
African / African-American	0.0133%	7,505
Admixed American	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,066
European (non-Finnish)	0.000678%	147,500

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.Pro348Leu
Coding: c.1043C>T
MANE Select: NM_001130823
dbSNP: rs370592431
Type: single nucleotide variant
Location: chr19:10160384 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 332 UniProt numbering: the 'interaction with the prc2/eed-ezh2 complex' region; the 'disordered' region; the 'homodimerization' 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: hereditary sensory neuropathy-deafness-dementia syndrome

Similar variants

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
DNMT1 c.*253G>A Uncertain significance ★★ same condition
DNMT1 p.Ala1053Thr 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-pro348leu (accessed [today's date]).

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