Is SDHA p.Ser8Ter (c.23C>A) pathogenic?

SDHA p.Ser8Ter (c.23C>A) is classified Pathogenic in SDHA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-21). Very rare (popmax 0.00143%, sas); Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Ser8Ter (c.23C>A)?

SDHA p.Ser8Ter (c.23C>A) is associated with mitochondrial complex II deficiency, nuclear type 1, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Ser8Ter (c.23C>A) in the general population?

SDHA p.Ser8Ter (c.23C>A) is very rare (popmax 0.00143%, sas) (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.Ser8Ter

c.23C>A · rs878854631 · VCV1451165

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00143%, sas)

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.81, phastCons 0.97
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00143% South Asian · 1/69,868 alleles

Overall 7.67e-05% 1/1,303,210 alleles · very rare

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.Ser8Ter
Coding: c.23C>A
MANE Select: NM_004168
dbSNP: rs878854631
Type: single nucleotide variant
Location: chr5:218378 (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

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.Ser8Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Ser8Trp Uncertain significance ★★ ⚠ same residue
SDHA p.Ser8= Benign/Likely benign ★★ same residue
SDHA p.Ser8Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Ser8Thr Uncertain significance ★ ⚠ same residue
SDHA p.Ser8_Arg9insGlyValArgGlyLeuSer Uncertain significance ★ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+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/sdha-p-ser8ter (accessed [today's date]).

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