Is SDHA p.Ser456= (c.1368G>A) pathogenic?

SDHA p.Ser456= (c.1368G>A) is classified Conflicting classifications of pathogenicity in SDHA (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-06-01). Rare (popmax 0.217%, nfe); Associated with neurodegeneration with ataxia and late-onset optic atrophy.

How common is SDHA p.Ser456= (c.1368G>A) in the general population?

SDHA p.Ser456= (c.1368G>A) is rare (popmax 0.217%, nfe) (gnomAD).

SDHA p.Ser456=

Q: What condition is associated with SDHA p.Ser456= (c.1368G>A)?

SDHA p.Ser456= (c.1368G>A) is associated with neurodegeneration with ataxia and late-onset optic atrophy, Leigh syndrome, dilated cardiomyopathy 1GG (ClinVar).

c.1368G>A · rs149875171 · VCV224948

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

rare (popmax 0.217%, nfe)

Conditions

neurodegeneration with ataxia and late-onset optic atrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.069	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	0.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.217% European (non-Finnish) · 2,561/1,179,878 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.18% 2,908/1,614,044 alleles · rare exomes 2,727/1,461,664 · genomes 181/152,380 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.217%	461
Remaining individualsnot grpmax-eligible	0.162%	619
South Asian	0.156%	641
Middle Eastern	0.116%	865
Admixed American	0.103%	968
African / African-American	0.0293%	3,412
Finnishnot grpmax-eligible	0.0187%	5,337
East Asian	0.00223%	44,886

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.Ser456=
Coding: c.1368G>A
MANE Select: NM_004168
dbSNP: rs149875171
Type: single nucleotide variant
Location: chr5:236535 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 456: an α-helix; a binding site

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

Disease context

neurodegeneration with ataxia and late-onset optic atrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

SDHA p.Ser456Ala Uncertain significance ★★ ⚠ same residue
SDHA p.Ser456Trp Uncertain significance ★★ ⚠ same residue
SDHA p.Ser456Ter Pathogenic ★ same residue
SDHA p.Ser456Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser456 (accessed [today's date]).

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