Is SDHA p.Ala466= (c.1398A>G) pathogenic?

SDHA p.Ala466= (c.1398A>G) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). Very rare (popmax 0.00167%, amr); Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Ala466= (c.1398A>G)?

SDHA p.Ala466= (c.1398A>G) is associated with mitochondrial complex II deficiency, nuclear type 1, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Ala466= (c.1398A>G) in the general population?

SDHA p.Ala466= (c.1398A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Isolated succinate-CoQ reductase deficiency inherited?

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

SDHA p.Ala466=

c.1398A>G · rs878854626 · VCV239645

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

mitochondrial complex II deficiency, nuclear type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.024	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.6
Overall
CADD	0.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000124% 2/1,613,916 alleles · very rare exomes 0/1,461,672 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00133%	74,936

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: SDHA
Protein: p.Ala466=
Coding: c.1398A>G
MANE Select: NM_004168
dbSNP: rs878854626
Type: single nucleotide variant
Location: chr5:236565 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 466: an α-helix

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

Disease context

mitochondrial complex II deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome

For Isolated succinate-CoQ reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SDHA p.Ala466Ser Uncertain significance ★★ ⚠ same residue
SDHA p.Ala466Pro Uncertain significance ★ ⚠ same residue
SDHA p.Ala466Thr Conflicting classifications of pathogenicity ★ same residue
SDHA p.Ala466Val Uncertain significance ★ ⚠ same residue
SDHA p.Ala466fs Pathogenic ★ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+1G>T Likely pathogenic ★★ same condition
SDHA c.1064+2T>A 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/sdha-p-ala466 (accessed [today's date]).

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