Is DNMT1 p.Phe648= (c.1944C>T) pathogenic?

DNMT1 p.Phe648= (c.1944C>T) is classified Benign in DNMT1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.7%, sas); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Phe648= (c.1944C>T)?

DNMT1 p.Phe648= (c.1944C>T) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Phe648= (c.1944C>T) in the general population?

DNMT1 p.Phe648= (c.1944C>T) is low-frequency (popmax 1.7%, sas) (gnomAD).

DNMT1 p.Phe648=

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.1944C>T · rs61750052 · VCV327907

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.7%, sas)

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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.48 · evaluated, not missing
Pangolin	Δ0.37	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 0.82	GERP -4.1, phastCons 0.99
Overall
CADD	14.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.7% South Asian · 1,553/91,088 alleles

Filtering AF 1.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 0.403% 6,508/1,614,236 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.7%	59
Remaining individualsnot grpmax-eligible	0.424%	236
European (non-Finnish)	0.366%	273
Middle Eastern	0.363%	276
Ashkenazi Jewishnot grpmax-eligible	0.284%	352
Admixed American	0.16%	625
Finnishnot grpmax-eligible	0.158%	634
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0839%	1,192
East Asian	0.00668%	14,960

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.Phe648=
Coding: c.1944C>T
MANE Select: NM_001130823
dbSNP: rs61750052
Type: single nucleotide variant
Location: chr19:10154368 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB

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.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-phe648 (accessed [today's date]).

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