Is SDHA p.Ala334= (c.1002G>A) pathogenic?

SDHA p.Ala334= (c.1002G>A) is classified Conflicting classifications of pathogenicity in SDHA (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-04-01). Rare (popmax 0.13%, nfe); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Ala334= (c.1002G>A)?

SDHA p.Ala334= (c.1002G>A) is associated with pheochromocytoma/paraganglioma syndrome 5, Leigh syndrome, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Ala334= (c.1002G>A) in the general population?

SDHA p.Ala334= (c.1002G>A) is rare (popmax 0.13%, nfe) (gnomAD).

SDHA p.Ala334=

c.1002G>A · rs144252500 · VCV252904

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.13%, nfe)

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -3.7
Overall
CADD	0.133	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.13% European (non-Finnish) · 1,538/1,180,028 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.104% 1,674/1,614,184 alleles · rare exomes 1,563/1,461,856 · genomes 111/152,328 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.13%	767
Finnishnot grpmax-eligible	0.0672%	1,489
Admixed American	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.0544%	1,839
African / African-American	0.016%	6,254
South Asian	0.0154%	6,506

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.Ala334=
Coding: c.1002G>A
MANE Select: NM_004168
dbSNP: rs144252500
Type: single nucleotide variant
Location: chr5:233583 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 334: a turn

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

Disease context

pheochromocytoma/paraganglioma syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Ala334Ser Uncertain significance ★★ same residue
SDHA p.Ala334Thr Uncertain significance ★★ ⚠ same residue
SDHA p.Ala334Val Uncertain significance ★★ ⚠ same residue
SDHA p.Ala334Gly Uncertain significance ★ ⚠ 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
SDHA c.1065-2A>G 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-ala334 (accessed [today's date]).

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