Is DLD p.Met438Thr (c.1313T>C) pathogenic?

DLD p.Met438Thr (c.1313T>C) is classified Uncertain significance in DLD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.413); Very rare (popmax 0.000254%, nfe); Associated with Leigh syndrome.

What condition is associated with DLD p.Met438Thr (c.1313T>C)?

DLD p.Met438Thr (c.1313T>C) is associated with Leigh syndrome, pyruvate dehydrogenase E3 deficiency, pyruvate dehydrogenase deficiency (ClinVar).

How common is DLD p.Met438Thr (c.1313T>C) in the general population?

DLD p.Met438Thr (c.1313T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Leigh syndrome inherited?

Typically Autosomal recessive, Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DLD p.Met438Thr (c.1313T>C)?

AlphaMissense predicts ambiguous (score 0.413) — an in-silico prediction, not a clinical call.

DLD p.Met438Thr

c.1313T>C · rs2032312825 · VCV911498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Leigh syndrome

Computational evidence

Protein change
AlphaMissense	0.413	ambiguous
REVEL	0.653	pathogenic-leaning
SaProt	LLR -11.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	26.4	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 0.000254% European (non-Finnish) · 3/1,179,956 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,782 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: DLD
Protein: p.Met438Thr
Coding: c.1313T>C
MANE Select: NM_000108
dbSNP: rs2032312825
Type: single nucleotide variant
Location: chr7:107918000 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 438: a β-strand

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

Disease context

Leigh syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E3 deficiency pyruvate dehydrogenase deficiency

For Leigh syndrome (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

DLD c.1464+1G>A Pathogenic/Likely pathogenic ★★ same condition
DLD c.198+1G>T Likely pathogenic ★★ same condition
DLD c.39+1G>A Likely pathogenic ★★ same condition
DLD c.40-2A>G Likely pathogenic ★★ same condition
DLD c.583-1G>C Likely pathogenic ★★ same condition
DLD c.684+1G>T Likely pathogenic ★★ same condition
DLD c.875+1G>A Pathogenic/Likely pathogenic ★★ same condition
DLD p.Arg315Ter Likely pathogenic ★★ 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/dld-p-met438thr (accessed [today's date]).

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