Is DCDC2 p.Val16Leu (c.46G>C) pathogenic?

DCDC2 p.Val16Leu (c.46G>C) is classified Uncertain significance in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-30). AlphaMissense: ambiguous (0.4693); Very rare (popmax 0.00136%, nfe).

How common is DCDC2 p.Val16Leu (c.46G>C) in the general population?

DCDC2 p.Val16Leu (c.46G>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about DCDC2 p.Val16Leu (c.46G>C)?

AlphaMissense predicts ambiguous (score 0.4693) — an in-silico prediction, not a clinical call.

DCDC2 p.Val16Leu

c.46G>C · VCV4072604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4693	ambiguous
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -6.77	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H22Q vs ClinVar V16L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,962 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,613,162 alleles · very rare

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: DCDC2
Protein: p.Val16Leu
Coding: c.46G>C
MANE Select: NM_016356
Type: single nucleotide variant
Location: chr6:24357705 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB

Full DCDC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCDC2 c.294-2A>G Pathogenic ★★ same type
DCDC2 c.349-2A>G Pathogenic ★★ same type
DCDC2 c.705-2A>G Pathogenic ★★ same type
DCDC2 p.Leu297Ter Pathogenic ★★ same type
DCDC2 p.Met1Arg Pathogenic/Likely pathogenic ★★ ⚠ same type
DCDC2 p.Ser128Ter Pathogenic/Likely pathogenic ★★ same type
DCDC2 p.Ala153Gly Uncertain significance ★★ same type
DCDC2 p.Ala356Pro 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/dcdc2-p-val16leu (accessed [today's date]).

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