Is LDHA p.Asp46Val (c.137A>T) pathogenic?

LDHA p.Asp46Val (c.137A>T) is classified Uncertain significance in LDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-30). AlphaMissense: likely pathogenic (0.7234); Very rare (popmax 0.00807%, nfe); Associated with glycogen storage disease due to lactate dehydrogenase M-subunit deficiency.

What condition is associated with LDHA p.Asp46Val (c.137A>T)?

LDHA p.Asp46Val (c.137A>T) is associated with glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (ClinVar).

How common is LDHA p.Asp46Val (c.137A>T) in the general population?

LDHA p.Asp46Val (c.137A>T) is very rare (popmax 0.00807%, nfe) (gnomAD).

What do computational predictors say about LDHA p.Asp46Val (c.137A>T)?

AlphaMissense predicts likely pathogenic (score 0.7234) — an in-silico prediction, not a clinical call.

LDHA p.Asp46Val

c.137A>T · rs201460924 · VCV879476

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00807%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

Computational evidence

Protein change
AlphaMissense	0.7234	likely pathogenic
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 10 kb · p 5.6e-12 · regional, not allelic
Overall
CADD	29.5	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 0.00807% European (non-Finnish) · 95/1,177,140 alleles

Filtering AF 0.00674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00626%

Overall 0.00615% 99/1,610,436 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00807%	12,391
Remaining individualsnot grpmax-eligible	0.00321%	31,160
Admixed American	0.00167%	59,984
African / African-American	0.00134%	74,852

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: LDHA
Protein: p.Asp46Val
Coding: c.137A>T
MANE Select: NM_005566
dbSNP: rs201460924
Type: single nucleotide variant
Location: chr11:18399441 (GRCh38)
Gene constraint: LOEUF 0.613 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 96.08 · 46 PDB
Residue 46: a binding site; a β-strand

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

Disease context

glycogen storage disease due to lactate dehydrogenase M-subunit deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDHA p.Asp46= Likely benign ★ same residue
LDHA p.Asp46Leu Uncertain significance ★ same residue
LDHA p.Ser137Ter Pathogenic ★★ same condition
LDHA c.*660C>T Uncertain significance ★★ same condition
LDHA p.Arg112Cys Uncertain significance ★★ ⚠ same condition
LDHA p.Arg157His Uncertain significance ★★ ⚠ same condition
LDHA p.Asp285Val Uncertain significance ★★ ⚠ same condition
LDHA p.Ile159Asn 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/ldha-p-asp46val (accessed [today's date]).

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