Is DLST p.Pro129Leu (c.386C>T) pathogenic?

DLST p.Pro129Leu (c.386C>T) is classified Uncertain significance in DLST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1989); Rare (popmax 0.132%, amr).

How common is DLST p.Pro129Leu (c.386C>T) in the general population?

DLST p.Pro129Leu (c.386C>T) is rare (popmax 0.132%, amr) (gnomAD).

What do computational predictors say about DLST p.Pro129Leu (c.386C>T)?

AlphaMissense predicts likely benign (score 0.1989) — an in-silico prediction, not a clinical call.

DLST p.Pro129Leu

c.386C>T · rs769413082 · VCV2337791

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1989 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1989	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.80 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 1,827 bp · p 2.3e-05 · regional, not allelic
Overall
CADD	32.0	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 0.132% Admixed American · 79/60,026 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0996%

Overall 0.0052% 84/1,614,082 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.132%	760
Remaining individualsnot grpmax-eligible	0.0048%	20,831
African / African-American	0.00133%	75,054
European (non-Finnish)	8.47e-05%	1,180,006

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: DLST
Protein: p.Pro129Leu
Coding: c.386C>T
MANE Select: NM_001933
dbSNP: rs769413082
Type: single nucleotide variant
Location: chr14:74891111 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.40 · 2 PDB
Residue 129: the lipoyl-binding domain

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

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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/dlst-p-pro129leu (accessed [today's date]).

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