Is DNMT3L p.Ala2Val (c.5C>T) pathogenic?

DNMT3L p.Ala2Val (c.5C>T) is classified Uncertain significance in DNMT3L (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.172); Very rare (popmax 0.00223%, eas).

How common is DNMT3L p.Ala2Val (c.5C>T) in the general population?

DNMT3L p.Ala2Val (c.5C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DNMT3L p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.172) — an in-silico prediction, not a clinical call.

DNMT3L p.Ala2Val

c.5C>T · rs776282345 · VCV2237497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.172	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.82	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 -0.17	GERP -1.8
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.69 · regional, not allelic
Overall
CADD	3.061	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00143% 23/1,612,176 alleles · very rare exomes 20/1,459,982 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,450
Finnishnot grpmax-eligible	0.0016%	62,542
European (non-Finnish)	0.00153%	65,545
African / African-American	0.00133%	74,924

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_175867
dbSNP: rs776282345
Type: single nucleotide variant
Location: chr21:44261255 (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.Ala244Thr Uncertain significance ★ ⚠ same type
DNMT3L p.Ala270Thr 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
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-ala2val (accessed [today's date]).

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