Is DCDC2B p.Arg74Ile (c.221G>T) pathogenic?

DCDC2B p.Arg74Ile (c.221G>T) is classified Uncertain significance in DCDC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely benign (0.3237); Rare (popmax 0.108%, afr).

How common is DCDC2B p.Arg74Ile (c.221G>T) in the general population?

DCDC2B p.Arg74Ile (c.221G>T) is rare (popmax 0.108%, afr) (gnomAD).

What do computational predictors say about DCDC2B p.Arg74Ile (c.221G>T)?

AlphaMissense predicts likely benign (score 0.3237) — an in-silico prediction, not a clinical call.

DCDC2B p.Arg74Ile

c.221G>T · VCV3500008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3237 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.108%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3237	likely benign
REVEL	0.498	indeterminate
SaProt	LLR -13.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,800 bp · p 0.21 · regional, not allelic
Overall
CADD	25.3	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 0.108% African / African-American · 81/75,040 alleles

Filtering AF 0.0889% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.082%

Overall 0.00545% 88/1,614,010 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.108%	926
Admixed American	0.00666%	15,007
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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: DCDC2B
Protein: p.Arg74Ile
Coding: c.221G>T
MANE Select: NM_001099434
Type: single nucleotide variant
Location: chr1:32209314 (GRCh38)
Gene constraint: LOEUF 1.383 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.12
Residue 74: the doublecortin 1 domain

Full DCDC2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCDC2B p.Ala125Pro Uncertain significance ★ ⚠ same type
DCDC2B p.Ala187Gly Uncertain significance ★ ⚠ same type
DCDC2B p.Ala239Ser Uncertain significance ★ ⚠ same type
DCDC2B p.Ala291Thr Uncertain significance ★ ⚠ same type
DCDC2B p.Ala346Val Uncertain significance ★ ⚠ same type
DCDC2B p.Ala55Ser Uncertain significance ★ ⚠ same type
DCDC2B p.Ala55Val Uncertain significance ★ ⚠ same type
DCDC2B p.Ala69Glu 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/dcdc2b-p-arg74ile (accessed [today's date]).

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