Is LDHB p.Pro293Ala (c.877C>G) pathogenic?

LDHB p.Pro293Ala (c.877C>G) is classified Uncertain significance in LDHB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: likely pathogenic (0.9734); Very rare (popmax 0.00446%, eas).

How common is LDHB p.Pro293Ala (c.877C>G) in the general population?

LDHB p.Pro293Ala (c.877C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LDHB p.Pro293Ala (c.877C>G)?

AlphaMissense predicts likely pathogenic (score 0.9734) — an in-silico prediction, not a clinical call.

LDHB p.Pro293Ala

c.877C>G · rs746055819 · VCV2525108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9734	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.01	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 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 19 kb · p 0.0018 · regional, not allelic
Overall
CADD	26.4	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 0.00446% East Asian · 2/44,864 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,613,682 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,432
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.000424%	235,975

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: LDHB
Protein: p.Pro293Ala
Coding: c.877C>G
MANE Select: NM_002300
dbSNP: rs746055819
Type: single nucleotide variant
Location: chr12:21635670 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05 · 7 PDB
Residue 293: a β-strand

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

Similar variants

LDHB p.Pro293= Benign ★★ same residue
LDHB p.Asn250Ser Uncertain significance ★★ ⚠ same type
LDHB p.Ile261Thr Uncertain significance ★★ ⚠ same type
LDHB p.Ser256Asn Uncertain significance ★★ ⚠ same type
LDHB c.713+15A>G Benign ★★ same type
LDHB c.129+11A>G Uncertain significance ★ same type
LDHB c.130-8G>A Conflicting classifications of pathogenicity ★ same type
LDHB c.421+7T>C Uncertain significance ★ 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/ldhb-p-pro293ala (accessed [today's date]).

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