Is SDHA p.Ser346= (c.1038C>G) pathogenic?

SDHA p.Ser346= (c.1038C>G) is classified Benign in SDHA (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 56.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHA p.Ser346= (c.1038C>G)?

SDHA p.Ser346= (c.1038C>G) is associated with hereditary pheochromocytoma-paraganglioma, Leigh syndrome, pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

How is Hereditary pheochromocytoma-paraganglioma inherited?

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

SDHA p.Ser346=

Q: How common is SDHA p.Ser346= (c.1038C>G) in the general population?

SDHA p.Ser346= (c.1038C>G) is common (popmax 56.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1038C>G · rs1041949 · VCV130273

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 56.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.61	GERP -3.7, phastCons 0.012
Overall
CADD	3.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.3% African / African-American · 42,175/74,912 alleles

Filtering AF 55.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 55.7%

Overall 14.8% 239,549/1,613,646 alleles · common exomes 201,643/1,461,520 · genomes 37,906/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	56.3%	2
Amishnot grpmax-eligible	30.5%	3
Admixed American	19.8%	5
Ashkenazi Jewishnot grpmax-eligible	17.6%	6
Remaining individualsnot grpmax-eligible	16.1%	6
Middle Eastern	14.5%	7
European (non-Finnish)	13%	8
South Asian	9.01%	11
Finnishnot grpmax-eligible	8.73%	11
East Asian	4.89%	20

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.Ser346=
Coding: c.1038C>G
MANE Select: NM_004168
dbSNP: rs1041949
Type: single nucleotide variant
Location: chr5:233619 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 346: an α-helix

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

Disease context

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHA p.Ser346Cys Uncertain significance ★★ ⚠ same residue
SDHA p.Ser346Ala Uncertain significance ★ ⚠ same residue
SDHA p.Ser346Phe Uncertain significance ★ ⚠ same residue
SDHA p.Ser346Tyr Uncertain significance ★ ⚠ same residue
SDHA p.Ser346Leu Uncertain significance ★★ same residue
SDHA p.Ser346fs Pathogenic ★ same residue
SDHA p.Ser346Trp Uncertain significance ★ same residue
SDHA c.1064+1G>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-ser346 (accessed [today's date]).

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