Is DNMT3A p.Leu648Pro (c.1943T>C) pathogenic?

DNMT3A p.Leu648Pro (c.1943T>C) is classified Pathogenic in DNMT3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-04-01). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 8.48e-05%, nfe); Associated with Tatton-Brown-Rahman overgrowth syndrome.

What condition is associated with DNMT3A p.Leu648Pro (c.1943T>C)?

DNMT3A p.Leu648Pro (c.1943T>C) is associated with Tatton-Brown-Rahman overgrowth syndrome (ClinVar).

How common is DNMT3A p.Leu648Pro (c.1943T>C) in the general population?

DNMT3A p.Leu648Pro (c.1943T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Leu648Pro (c.1943T>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

DNMT3A p.Leu648Pro

c.1943T>C · rs587777507 · VCV139616

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tatton-Brown-Rahman overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 7% in DNMT3A
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -12.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 4,806 bp · p 8.9e-10 · regional, not allelic
Overall
CADD	32.0	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) · 1/1,179,886 alleles

Overall 6.84e-05% 1/1,461,464 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.Leu648Pro
Coding: c.1943T>C
MANE Select: NM_022552
dbSNP: rs587777507
Type: single nucleotide variant
Location: chr2:25241701 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 648: an α-helix; the sam-dependent mtase c5-type domain; a UniProt-annotated variant site (in tbrs; somatic mutation)

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

Disease context

Tatton-Brown-Rahman overgrowth syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg598Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg688His 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-leu648pro (accessed [today's date]).

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