Is SDHA p.Ser2= (c.6G>A) pathogenic?

SDHA p.Ser2= (c.6G>A) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-13). Very rare (popmax 0.00276%, eas); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Ser2= (c.6G>A)?

SDHA p.Ser2= (c.6G>A) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Ser2= (c.6G>A) in the general population?

SDHA p.Ser2= (c.6G>A) is very rare (popmax 0.00276%, eas) (gnomAD).

SDHA p.Ser2=

c.6G>A · rs751383247 · VCV793653

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00276%, eas)

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 -4.2	GERP -2.6
Overall
CADD	3.933	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00276% East Asian · 1/36,234 alleles

Overall 0.000137% 2/1,461,142 alleles · very rare exomes 2/1,308,840 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00276%	36,234
African / African-American	0.00146%	68,474

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.Ser2=
Coding: c.6G>A
MANE Select: NM_004168
dbSNP: rs751383247
Type: single nucleotide variant
Location: chr5:218361 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB

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: hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Ser2Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Ser2Ter Pathogenic ★ same residue
SDHA p.Ser2Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Ser2Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Ser2Trp 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

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-ser2 (accessed [today's date]).

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