Is DNMT3A p.Arg183Trp (c.547C>T) pathogenic?

DNMT3A p.Arg183Trp (c.547C>T) is classified Uncertain significance in DNMT3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely pathogenic (0.8063); Very rare (popmax 0.00111%, sas).

How common is DNMT3A p.Arg183Trp (c.547C>T) in the general population?

DNMT3A p.Arg183Trp (c.547C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about DNMT3A p.Arg183Trp (c.547C>T)?

AlphaMissense predicts likely pathogenic (score 0.8063) — an in-silico prediction, not a clinical call.

DNMT3A p.Arg183Trp

c.547C>T · rs1311728146 · VCV2572932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8063	likely pathogenic
REVEL	0.703	pathogenic-leaning
SaProt	LLR -11.19	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 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 27 kb · p 6.6e-12 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/89,820 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,454,024 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,820
European (non-Finnish)	0.00017%	588,481

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.Arg183Trp
Coding: c.547C>T
MANE Select: NM_022552
dbSNP: rs1311728146
Type: single nucleotide variant
Location: chr2:25275033 (GRCh38)
Gene constraint: LOEUF 1.998 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.97 · 47 PDB

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

Similar variants

DNMT3A c.1667+1G>A Likely pathogenic ★★ same type
DNMT3A c.1937-2A>G Pathogenic ★★ same type
DNMT3A c.2478+1G>A Pathogenic/Likely pathogenic ★★ same type
DNMT3A c.2479-1G>A Likely pathogenic ★★ same type
DNMT3A p.Arg143Ter Pathogenic ★★ same type
DNMT3A p.Arg301Trp Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Arg320Ter Pathogenic/Likely pathogenic ★★ same type
DNMT3A p.Arg598Ter Pathogenic/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-arg183trp (accessed [today's date]).

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