Is DNMT1 p.Cys41Arg (c.121T>C) pathogenic?

DNMT1 p.Cys41Arg (c.121T>C) is classified Uncertain significance in DNMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: ambiguous (0.4707); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.Cys41Arg (c.121T>C)?

DNMT1 p.Cys41Arg (c.121T>C) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

How common is DNMT1 p.Cys41Arg (c.121T>C) in the general population?

DNMT1 p.Cys41Arg (c.121T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DNMT1 p.Cys41Arg (c.121T>C)?

AlphaMissense predicts ambiguous (score 0.4707) — an in-silico prediction, not a clinical call.

DNMT1 p.Cys41Arg

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.121T>C · rs1218241317 · VCV2916941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
AlphaMissense	0.4707	ambiguous
REVEL	0.199	benign-leaning
SaProt	LLR -2.39	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 6.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	23.0	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 8.48e-05% European (non-Finnish) · 1/1,179,782 alleles

Overall 6.2e-05% 1/1,613,898 alleles · very rare exomes 1/1,461,584 · genomes 0/152,314 · 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.Cys41Arg
Coding: c.121T>C
MANE Select: NM_001130823
dbSNP: rs1218241317
Type: single nucleotide variant
Location: chr19:10180882 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 41: the dmap1-binding domain; the 'interaction with the prc2/eed-ezh2 complex' region; an α-helix; the 'interaction with dnmt3a' region; the 'interaction with dmap1' 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.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-cys41arg (accessed [today's date]).

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