Is DNMT3A p.Arg771Ter (c.2311C>T) pathogenic?

DNMT3A p.Arg771Ter (c.2311C>T) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-12). Very rare (popmax 0.00415%, nfe); Associated with DNMT3A-related disorder.

What condition is associated with DNMT3A p.Arg771Ter (c.2311C>T)?

DNMT3A p.Arg771Ter (c.2311C>T) is associated with DNMT3A-related disorder, Tatton-Brown-Rahman overgrowth syndrome, acute myeloid leukemia (ClinVar).

How common is DNMT3A p.Arg771Ter (c.2311C>T) in the general population?

DNMT3A p.Arg771Ter (c.2311C>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

DNMT3A p.Arg771Ter

c.2311C>T · rs779626155 · VCV419534

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Conditions

DNMT3A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 19 of 23
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Overall
CADD	45.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,179,842 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00378% 61/1,613,788 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,793
Finnishnot grpmax-eligible	0.00469%	21,333
European (non-Finnish)grpmax	0.00415%	24,078
African / African-American	0.004%	24,973
East Asian	0.00223%	44,892
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,082

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg771Ter
Coding: c.2311C>T
MANE Select: NM_022552
dbSNP: rs779626155
Type: single nucleotide variant
Location: chr2:25240313 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 771: an α-helix; the sam-dependent mtase c5-type domain; a UniProt-annotated variant site (in tbrs; uncertain significance)

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

Disease context

DNMT3A-related disorder

Also linked: Tatton-Brown-Rahman overgrowth syndrome acute myeloid leukemia

Similar variants

DNMT3A p.Arg771Gln Pathogenic/Likely pathogenic ★★ same residue
DNMT3A p.Arg771Gly Likely pathogenic ★ same residue
DNMT3A p.Arg771fs Pathogenic ★ same residue
DNMT3A p.Arg771Leu Uncertain significance ★ ⚠ same residue
DNMT3A c.1667+1G>A Likely pathogenic ★★ same condition
DNMT3A c.1937-2A>G Pathogenic ★★ same condition
DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNMT3A c.2479-1G>A Likely pathogenic ★★ 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/dnmt3a-p-arg771ter (accessed [today's date]).

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