Is DNMT1 p.Pro131= (c.393C>T) pathogenic?

DNMT1 p.Pro131= (c.393C>T) is classified Benign/Likely benign in DNMT1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0495%, mid); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Pro131= (c.393C>T)?

DNMT1 p.Pro131= (c.393C>T) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Pro131= (c.393C>T) in the general population?

DNMT1 p.Pro131= (c.393C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

DNMT1 p.Pro131=

Q: How is Hereditary sensory neuropathy-deafness-dementia syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.393C>T · rs143904813 · VCV327925

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -0.65
Overall
CADD	1.129	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0321% 518/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
European (non-Finnish)	0.0408%	2,448
Remaining individualsnot grpmax-eligible	0.024%	4,167
African / African-American	0.0147%	6,821
Admixed American	0.00834%	11,996
Finnishnot grpmax-eligible	0.00313%	31,948

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.Pro131=
Coding: c.393C>T
MANE Select: NM_001130823
dbSNP: rs143904813
Type: single nucleotide variant
Location: chr19:10180402 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 131: 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

hereditary sensory neuropathy-deafness-dementia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory neuropathy-deafness-dementia syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DNMT1 p.Pro131Ser Uncertain significance ★★ ⚠ 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
DNMT1 c.*253G>A 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-pro131 (accessed [today's date]).

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