Is DNMT1 p.His97Arg (c.290A>G) pathogenic?

DNMT1 p.His97Arg (c.290A>G) is classified Benign/Likely benign in DNMT1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0664); Common (popmax 19%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary sensory neuropathy-deafness-dementia syndrome.

What condition is associated with DNMT1 p.His97Arg (c.290A>G)?

DNMT1 p.His97Arg (c.290A>G) is associated with hereditary sensory neuropathy-deafness-dementia syndrome (ClinVar).

What do computational predictors say about DNMT1 p.His97Arg (c.290A>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

DNMT1 p.His97Arg

Q: How common is DNMT1 p.His97Arg (c.290A>G) in the general population?

DNMT1 p.His97Arg (c.290A>G) is common (popmax 19%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.290A>G · rs16999593 · VCV257539

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary sensory neuropathy-deafness-dementia syndrome

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -5.72	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 0.61	GERP 2.7, phastCons 0.37
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.0067 · regional, not allelic
Overall
CADD	12.41	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 19% East Asian · 8,513/44,870 alleles

Filtering AF 18.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.5%

Overall 0.824% 13,306/1,614,168 alleles · common exomes 11,484/1,461,894 · genomes 1,822/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	19%	5
Admixed American	5.1%	20
Remaining individualsnot grpmax-eligible	1.34%	75
South Asian	0.536%	187
African / African-American	0.219%	458
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
Middle Eastern	0.099%	1,010
European (non-Finnish)	0.0168%	5,960
Finnishnot grpmax-eligible	0.00468%	21,346

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.His97Arg
Coding: c.290A>G
MANE Select: NM_001130823
dbSNP: rs16999593
Type: single nucleotide variant
Location: chr19:10180505 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 29 PDB
Residue 97: the dmap1-binding domain; a UniProt-annotated variant site (in); the 'interaction with the prc2/eed-ezh2 complex' region; 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.His97Tyr 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-his97arg (accessed [today's date]).

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