Is LDHA p.Pro129Arg (c.386C>G) pathogenic?

LDHA p.Pro129Arg (c.386C>G) is classified Uncertain significance in LDHA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-12). AlphaMissense: ambiguous (0.4131); Very rare (popmax 0.00769%, sas); Associated with glycogen storage disease due to lactate dehydrogenase M-subunit deficiency.

What condition is associated with LDHA p.Pro129Arg (c.386C>G)?

LDHA p.Pro129Arg (c.386C>G) is associated with glycogen storage disease due to lactate dehydrogenase M-subunit deficiency (ClinVar).

How common is LDHA p.Pro129Arg (c.386C>G) in the general population?

LDHA p.Pro129Arg (c.386C>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about LDHA p.Pro129Arg (c.386C>G)?

AlphaMissense predicts ambiguous (score 0.4131) — an in-silico prediction, not a clinical call.

LDHA p.Pro129Arg

c.386C>G · rs754439498 · VCV1969308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

Computational evidence

Protein change
AlphaMissense	0.4131	ambiguous
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -14.98	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 10 kb · p 5.6e-12 · regional, not allelic
Overall
CADD	27.6	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 0.00769% South Asian · 7/91,044 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000958% 14/1,461,454 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,006
Remaining individualsnot grpmax-eligible	0.0032%	31,235
European (non-Finnish)	0.000424%	235,925

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.Pro129Arg
Coding: c.386C>G
MANE Select: NM_005566
dbSNP: rs754439498
Type: single nucleotide variant
Location: chr11:18400978 (GRCh38)
Gene constraint: LOEUF 0.613 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 96.08 · 46 PDB

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.Pro129= Benign ★★ same residue
LDHA p.Pro129Leu 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.Asp46Val 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-pro129arg (accessed [today's date]).

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