Is DNMT3L p.Arg331Lys (c.992G>A) pathogenic?

DNMT3L p.Arg331Lys (c.992G>A) is classified Likely benign in DNMT3L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely benign (0.0945); Absent from gnomAD v4.1.

How common is DNMT3L p.Arg331Lys (c.992G>A) in the general population?

DNMT3L p.Arg331Lys (c.992G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNMT3L p.Arg331Lys (c.992G>A)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

DNMT3L p.Arg331Lys

c.992G>A · VCV3504269

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.9
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.69 · regional, not allelic
Overall
CADD	0.305	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.Arg331Lys
Coding: c.992G>A
MANE Select: NM_175867
Type: single nucleotide variant
Location: chr21:44249029 (GRCh38)
Gene constraint: LOEUF 1.179 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.47 · 29 PDB
Residue 331: an α-helix

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

Similar variants

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
DNMT3L p.Arg161Ser 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-arg331lys (accessed [today's date]).

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