Is DNMT3A p.Tyr623fs (c.1867dup) pathogenic?

DNMT3A p.Tyr623fs (c.1867dup) is classified Likely pathogenic in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-13). Very rare (popmax 7.14e-05%).

How common is DNMT3A p.Tyr623fs (c.1867dup) in the general population?

DNMT3A p.Tyr623fs (c.1867dup) is very rare (popmax 7.14e-05%) (gnomAD).

DNMT3A p.Tyr623fs

c.1867dup · rs1553412022 · VCV503964

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 7.14e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 16 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.14e-05%

Overall 7.14e-05% 1/1,401,396 alleles · very rare

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: DNMT3A
Protein: p.Tyr623fs
Coding: c.1867dup
MANE Select: NM_022552
dbSNP: rs1553412022
Type: Duplication
Location: chr2:25243966 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 623: an α-helix

Full DNMT3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNMT3A p.Tyr623= Likely benign ★ same residue
DNMT3A p.Ala571fs Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Val60fs Pathogenic ★★ same type
DNMT3A p.Ala114fs Pathogenic ★ same type
DNMT3A p.Ala45fs Likely pathogenic ★ same type
DNMT3A p.Arg659fs Likely pathogenic ★ same type
DNMT3A p.Arg771fs Pathogenic ★ same type
DNMT3A p.Gln485fs Likely pathogenic ★ same type

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/dnmt3a-p-tyr623fs (accessed [today's date]).

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