Is DBF4B p.Val223Ala (c.668T>C) pathogenic?

DBF4B p.Val223Ala (c.668T>C) is classified Uncertain significance in DBF4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.3645); Very rare (popmax 8.48e-05%, nfe).

How common is DBF4B p.Val223Ala (c.668T>C) in the general population?

DBF4B p.Val223Ala (c.668T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DBF4B p.Val223Ala (c.668T>C)?

AlphaMissense predicts ambiguous (score 0.3645) — an in-silico prediction, not a clinical call.

DBF4B p.Val223Ala

c.668T>C · VCV4237688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3645	ambiguous
REVEL	0.097	moderately benign-leaning
SaProt	LLR -4.01	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 21 kb · p 0.0076 · regional, not allelic
Overall
CADD	16.46	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 8.48e-05% European (non-Finnish) · 1/1,179,572 alleles

Overall 6.84e-05% 1/1,461,178 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: DBF4B
Protein: p.Val223Ala
Coding: c.668T>C
MANE Select: NM_145663
Type: single nucleotide variant
Location: chr17:44738379 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.60

Full DBF4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DBF4B p.Val89Met Uncertain significance ★★ ⚠ same type
DBF4B p.Ala197Val Uncertain significance ★ ⚠ same type
DBF4B p.Ala331Val Uncertain significance ★ ⚠ same type
DBF4B p.Ala361Thr Uncertain significance ★ ⚠ same type
DBF4B p.Ala383Thr Uncertain significance ★ ⚠ same type
DBF4B p.Ala499Ser Uncertain significance ★ ⚠ same type
DBF4B p.Ala69Thr Uncertain significance ★ ⚠ same type
DBF4B p.Arg131Ser 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/dbf4b-p-val223ala (accessed [today's date]).

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