Is SDHA p.Arg451= (c.1353C>G) pathogenic?

SDHA p.Arg451= (c.1353C>G) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0183%, amr); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Arg451= (c.1353C>G)?

SDHA p.Arg451= (c.1353C>G) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Arg451= (c.1353C>G) in the general population?

SDHA p.Arg451= (c.1353C>G) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

SDHA p.Arg451=

c.1353C>G · rs555342133 · VCV486366

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.016	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -3.6
Overall
CADD	0.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,024 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000867% 14/1,614,050 alleles · ultra-rare exomes 9/1,461,662 · genomes 5/152,388 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,892

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.Arg451=
Coding: c.1353C>G
MANE Select: NM_004168
dbSNP: rs555342133
Type: single nucleotide variant
Location: chr5:236520 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 451: a binding site; a UniProt-annotated variant site (in ndaxoa)

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.Arg451Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Arg451Leu Likely pathogenic ★ same residue
SDHA p.Arg451Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Arg451His Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Arg451Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Arg451Gly 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-arg451 (accessed [today's date]).

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