Is DLD p.Arg263His (c.788G>A) pathogenic?

DLD p.Arg263His (c.788G>A) is classified Conflicting classifications of pathogenicity in DLD (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.4251); Rare (popmax 0.207%, amr); Associated with Inborn genetic diseases.

What condition is associated with DLD p.Arg263His (c.788G>A)?

DLD p.Arg263His (c.788G>A) is associated with Inborn genetic diseases, pyruvate dehydrogenase E3 deficiency, Leigh syndrome (ClinVar).

How common is DLD p.Arg263His (c.788G>A) in the general population?

DLD p.Arg263His (c.788G>A) is rare (popmax 0.207%, amr) (gnomAD).

What do computational predictors say about DLD p.Arg263His (c.788G>A)?

AlphaMissense predicts ambiguous (score 0.4251) — an in-silico prediction, not a clinical call.

DLD p.Arg263His

c.788G>A · rs145670503 · VCV203681

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.4251 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.207%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4251	ambiguous
REVEL	0.505	indeterminate
SaProt	LLR -11.75	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 28 kb · p 0.0061 · regional, not allelic
Overall
CADD	29.6	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 0.207% Admixed American · 124/59,964 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.0871% 1,406/1,613,550 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.207%	484
European (non-Finnish)	0.0976%	1,024
Remaining individualsnot grpmax-eligible	0.096%	1,041
Finnishnot grpmax-eligible	0.0719%	1,391
African / African-American	0.0253%	3,947
East Asian	0.0067%	14,933
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
South Asian	0.0011%	91,042

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.Arg263His
Coding: c.788G>A
MANE Select: NM_000108
dbSNP: rs145670503
Type: single nucleotide variant
Location: chr7:107915609 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.69 · 17 PDB
Residue 263: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E3 deficiency Leigh syndrome pyruvate dehydrogenase deficiency

Similar variants

DLD p.Arg263Cys Uncertain significance ★ ⚠ same residue
DLD p.Arg263= Likely benign ★ same residue
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

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-arg263his (accessed [today's date]).

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