Is DNMT3L p.Arg161Ser (c.481C>A) pathogenic?

DNMT3L p.Arg161Ser (c.481C>A) is classified Uncertain significance in DNMT3L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.8307); Rare (popmax 0.118%, afr).

How common is DNMT3L p.Arg161Ser (c.481C>A) in the general population?

DNMT3L p.Arg161Ser (c.481C>A) is rare (popmax 0.118%, afr) (gnomAD).

What do computational predictors say about DNMT3L p.Arg161Ser (c.481C>A)?

AlphaMissense predicts likely pathogenic (score 0.8307) — an in-silico prediction, not a clinical call.

DNMT3L p.Arg161Ser

c.481C>A · VCV3841817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8307 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.118%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8307	likely pathogenic
REVEL	0.323	indeterminate
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.026, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.69 · regional, not allelic
Overall
CADD	21.9	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 0.118% African / African-American · 88/74,754 alleles

Filtering AF 0.0978% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0905%

Overall 0.00645% 103/1,597,650 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.118%	849
Remaining individualsnot grpmax-eligible	0.0129%	7,732
South Asian	0.00449%	22,264
Admixed American	0.00348%	28,762
European (non-Finnish)	8.53e-05%	1,172,692

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: DNMT3L
Protein: p.Arg161Ser
Coding: c.481C>A
MANE Select: NM_175867
Type: single nucleotide variant
Location: chr21:44258558 (GRCh38)
Gene constraint: LOEUF 1.179 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.47 · 29 PDB
Residue 161: the add domain; an α-helix

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

Similar variants

DNMT3L p.Arg161His 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.Arg254Cys 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-arg161ser (accessed [today's date]).

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