Is DBT p.Ser70Leu (c.209C>T) pathogenic?

DBT p.Ser70Leu (c.209C>T) is classified Uncertain significance in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2013-09-04). AlphaMissense: likely pathogenic (0.6976); Very rare (popmax 8.57e-05%, nfe).

How common is DBT p.Ser70Leu (c.209C>T) in the general population?

DBT p.Ser70Leu (c.209C>T) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about DBT p.Ser70Leu (c.209C>T)?

AlphaMissense predicts likely pathogenic (score 0.6976) — an in-silico prediction, not a clinical call.

DBT p.Ser70Leu

c.209C>T · rs398123664 · VCV93997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6976	likely pathogenic
REVEL	0.534	indeterminate
SaProt	LLR -14.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.57e-05% European (non-Finnish) · 1/1,166,822 alleles

Overall 6.92e-05% 1/1,445,952 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: DBT
Protein: p.Ser70Leu
Coding: c.209C>T
MANE Select: NM_001918
dbSNP: rs398123664
Type: single nucleotide variant
Location: chr1:100235478 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB
Residue 70: the lipoyl-binding domain

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

Similar variants

DBT p.Ser70Ter Likely pathogenic ★ same residue
DBT c.1018-550A>G Pathogenic/Likely pathogenic ★★ same type
DBT c.1281+1G>A Pathogenic/Likely pathogenic ★★ same type
DBT c.1281+1G>T Pathogenic/Likely pathogenic ★★ same type
DBT c.51+1G>T Pathogenic/Likely pathogenic ★★ same type
DBT c.52-1G>A Pathogenic/Likely pathogenic ★★ same type
DBT c.773-2A>G Pathogenic ★★ same type
DBT p.Arg169Ter Pathogenic/Likely pathogenic ★★ 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/dbt-p-ser70leu (accessed [today's date]).

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