Is DCDC2 p.Ser253Cys (c.757A>T) pathogenic?

DCDC2 p.Ser253Cys (c.757A>T) is classified Uncertain significance in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0841); Very rare (popmax 0.00167%, amr).

How common is DCDC2 p.Ser253Cys (c.757A>T) in the general population?

DCDC2 p.Ser253Cys (c.757A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DCDC2 p.Ser253Cys (c.757A>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

DCDC2 p.Ser253Cys

c.757A>T · VCV3378169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Pangolin	Δ0.21	loss · gain 0.18 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	28.3	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 0.00167% Admixed American · 1/59,904 alleles

Overall 6.85e-05% 1/1,459,444 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.Ser253Cys
Coding: c.757A>T
MANE Select: NM_016356
Type: single nucleotide variant
Location: chr6:24288854 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 253: a UniProt-annotated variant site (in nsc); the 'disordered' region

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-ser253cys (accessed [today's date]).

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