Is DNMT3L p.Ser339Trp (c.1016C>G) pathogenic?

DNMT3L p.Ser339Trp (c.1016C>G) is classified Uncertain significance in DNMT3L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1734); Absent from gnomAD v4.1.

How common is DNMT3L p.Ser339Trp (c.1016C>G) in the general population?

DNMT3L p.Ser339Trp (c.1016C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3L p.Ser339Trp (c.1016C>G)?

AlphaMissense predicts likely benign (score 0.1734) — an in-silico prediction, not a clinical call.

DNMT3L p.Ser339Trp

c.1016C>G · VCV4243655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1734 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1734	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -12.74	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.1	GERP -0.39, phastCons 0.96
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.69 · regional, not allelic
Overall
CADD	18.21	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNMT3L
Protein: p.Ser339Trp
Coding: c.1016C>G
MANE Select: NM_175867
Type: single nucleotide variant
Location: chr21:44246542 (GRCh38)
Gene constraint: LOEUF 1.179 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.47 · 29 PDB

Full DNMT3L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNMT3L p.Ser339Leu Uncertain significance ★ ⚠ same residue
DNMT3L p.Ala244Thr Uncertain significance ★ ⚠ same type
DNMT3L p.Ala270Thr Uncertain significance ★ ⚠ same type
DNMT3L p.Ala2Val Uncertain significance ★ ⚠ same type
DNMT3L p.Ala356Val Uncertain significance ★ ⚠ same type
DNMT3L p.Arg157Trp Uncertain significance ★ same type
DNMT3L p.Arg158Lys Uncertain significance ★ ⚠ same type
DNMT3L p.Arg161His Uncertain significance ★ ⚠ 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/dnmt3l-p-ser339trp (accessed [today's date]).

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