Is SDHA p.Pro658= (c.1974G>C) pathogenic?

SDHA p.Pro658= (c.1974G>C) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-02). Rare (popmax 0.658%, mid); Associated with neurodegeneration with ataxia and late-onset optic atrophy.

How common is SDHA p.Pro658= (c.1974G>C) in the general population?

SDHA p.Pro658= (c.1974G>C) is rare (popmax 0.658%, mid) (gnomAD).

SDHA p.Pro658=

Q: What condition is associated with SDHA p.Pro658= (c.1974G>C)?

SDHA p.Pro658= (c.1974G>C) is associated with neurodegeneration with ataxia and late-onset optic atrophy, Leigh syndrome, dilated cardiomyopathy 1GG (ClinVar).

c.1974G>C · rs1042446 · VCV252907

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.658%, mid)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.1, phastCons 0.001
Overall
CADD	1.075	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.658% Middle Eastern · 30/4,556 alleles

Filtering AF 0.474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.411%

Overall 0.344% 4,604/1,340,196 alleles · rare exomes 4,311/1,198,342 · genomes 293/141,854 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.658%	152
African / African-American	0.401%	249
European (non-Finnish)	0.394%	254
Remaining individualsnot grpmax-eligible	0.318%	314
Admixed American	0.279%	358
Amishnot grpmax-eligible	0.23%	434
Finnishnot grpmax-eligible	0.155%	645
Ashkenazi Jewishnot grpmax-eligible	0.113%	885
East Asian	0.101%	987
South Asian	0.0897%	1,115

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.Pro658=
Coding: c.1974G>C
MANE Select: NM_004168
dbSNP: rs1042446
Type: single nucleotide variant
Location: chr5:256399 (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

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.Pro658Ala Uncertain significance ★ ⚠ same residue
SDHA p.Pro658Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Pro658Ser Uncertain significance ★ ⚠ same residue
SDHA p.Pro658Thr 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-pro658 (accessed [today's date]).

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