Is DBT p.Pro245Leu (c.734C>T) pathogenic?

DBT p.Pro245Leu (c.734C>T) is classified Uncertain significance in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0618); Ultra-rare (popmax 0.0112%, eas); Associated with Inborn genetic diseases.

What condition is associated with DBT p.Pro245Leu (c.734C>T)?

DBT p.Pro245Leu (c.734C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DBT p.Pro245Leu (c.734C>T) in the general population?

DBT p.Pro245Leu (c.734C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about DBT p.Pro245Leu (c.734C>T)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

DBT p.Pro245Leu

c.734C>T · VCV4616967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.27	GERP -0.16, phastCons 0.003
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	10.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,814 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00292% 47/1,611,350 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,963
African / African-American	0.0107%	9,360
Remaining individualsnot grpmax-eligible	0.0032%	31,204
European (non-Finnish)	0.00246%	40,612
South Asian	0.0022%	45,511
Admixed American	0.00167%	59,978

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: DBT
Protein: p.Pro245Leu
Coding: c.734C>T
MANE Select: NM_001918
Type: single nucleotide variant
Location: chr1:100216021 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB

Full DBT 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

DBT p.Pro245Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
DBT p.Pro245= Likely benign ★ same residue
DBT c.1281+5A>G Uncertain significance ★★ same condition
DBT p.Arg61Cys Uncertain significance ★★ ⚠ same condition
DBT p.Cys279Phe Uncertain significance ★★ ⚠ same condition
DBT p.Thr171Ile Uncertain significance ★★ ⚠ same condition
DBT p.Thr407Ala Uncertain significance ★★ ⚠ same condition
DBT p.Asn326= Likely benign ★★ 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/dbt-p-pro245leu (accessed [today's date]).

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