Is DNMT3A p.Phe331= (c.993C>T) pathogenic?

DNMT3A p.Phe331= (c.993C>T) is classified Likely benign in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-23). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Phe331= (c.993C>T)?

DNMT3A p.Phe331= (c.993C>T) is associated with Inborn genetic diseases, Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Phe331= (c.993C>T) in the general population?

DNMT3A p.Phe331= (c.993C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

DNMT3A p.Phe331=

c.993C>T · rs151221034 · VCV1914836

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.03	GERP -1.4, phastCons 0.36
Overall
CADD	11.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00118% 19/1,613,766 alleles · very rare exomes 16/1,461,818 · genomes 3/151,948 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,985
Finnishnot grpmax-eligible	0.00156%	63,980
African / African-American	0.00134%	74,808
European (non-Finnish)	0.00119%	84,285
South Asian	0.0011%	91,064

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.Phe331=
Coding: c.993C>T
MANE Select: NM_022552
dbSNP: rs151221034
Type: single nucleotide variant
Location: chr2:25247612 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 331: the pwwp domain; a turn; the 'interaction with dnmt1 and dnmt3b' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tatton-Brown-Rahman overgrowth syndrome

Similar variants

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
DNMT3A p.Arg143Ter Pathogenic ★★ same condition
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter Pathogenic/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-phe331 (accessed [today's date]).

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