Is DBR1 p.Ser423Pro (c.1267T>C) pathogenic?

DBR1 p.Ser423Pro (c.1267T>C) is classified Uncertain significance in DBR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.568); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with DBR1 p.Ser423Pro (c.1267T>C)?

DBR1 p.Ser423Pro (c.1267T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DBR1 p.Ser423Pro (c.1267T>C) in the general population?

DBR1 p.Ser423Pro (c.1267T>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about DBR1 p.Ser423Pro (c.1267T>C)?

AlphaMissense predicts likely pathogenic (score 0.568) — an in-silico prediction, not a clinical call.

DBR1 p.Ser423Pro

c.1267T>C · rs897912837 · VCV3080210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.568	likely pathogenic
REVEL	0.128	moderately benign-leaning
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 490 bp · p 0.31 · regional, not allelic
Overall
CADD	23.8	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 0.01% Admixed American · 6/60,010 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000682% 11/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000339%	295,004

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: DBR1
Protein: p.Ser423Pro
Coding: c.1267T>C
MANE Select: NM_016216
dbSNP: rs897912837
Type: single nucleotide variant
Location: chr3:138162257 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.04
Residue 423: the 'disordered' region; a UniProt-annotated variant site (in iiae11; loss of protein expression)

Full DBR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DBR1 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
DBR1 p.Ala443Thr Uncertain significance ★★ ⚠ same condition
DBR1 p.Ala458Asp Uncertain significance ★★ ⚠ same condition
DBR1 p.Arg197Gln Uncertain significance ★★ ⚠ same condition
DBR1 p.Arg527Ser Uncertain significance ★★ ⚠ same condition
DBR1 p.Glu434Asp Uncertain significance ★★ ⚠ same condition
DBR1 p.Gly121Ser Uncertain significance ★★ ⚠ same condition
DBR1 p.Gly27Ser Uncertain significance ★★ ⚠ same condition

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/dbr1-p-ser423pro (accessed [today's date]).

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