Is DNMT3A p.Met548Thr (c.1643T>C) pathogenic?

DNMT3A p.Met548Thr (c.1643T>C) is classified Pathogenic/Likely pathogenic in DNMT3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-22). AlphaMissense: likely pathogenic (0.9997); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNMT3A p.Met548Thr (c.1643T>C)?

DNMT3A p.Met548Thr (c.1643T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DNMT3A p.Met548Thr (c.1643T>C) in the general population?

DNMT3A p.Met548Thr (c.1643T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DNMT3A p.Met548Thr (c.1643T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

DNMT3A p.Met548Thr

c.1643T>C · rs587777509 · VCV985328

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 7% in DNMT3A
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -15.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,445 bp · p 4.3e-09 · regional, not allelic
Overall
CADD	27.8	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 0.000339% European (non-Finnish) · 4/1,179,996 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,840 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)grpmax	0.000339%	294,999

Remaining individuals 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.Met548Thr
Coding: c.1643T>C
MANE Select: NM_022552
dbSNP: rs587777509
Type: single nucleotide variant
Location: chr2:25244564 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB
Residue 548: the 'interaction with the prc2/eed-ezh2 complex' region; the add domain; a UniProt-annotated variant site (in tbrs; somatic mutation); a β-strand

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

Similar variants

DNMT3A p.Met548Lys Pathogenic same residue
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Arg688His Pathogenic/Likely pathogenic ★★ same condition
DNMT3A p.Pro904Leu Pathogenic/Likely pathogenic ★★ same condition
DNMT3A c.448+48C>G Uncertain significance ★★ same condition
DNMT3A p.Arg544His Uncertain significance ★★ ⚠ same condition
DNMT3A p.Arg596Gln 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/dnmt3a-p-met548thr (accessed [today's date]).

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