Is SDHAF2 p.Arg33= (c.99C>T) pathogenic?

SDHAF2 p.Arg33= (c.99C>T) is classified Likely benign in SDHAF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-06). Ultra-rare (popmax 0.0165%, sas); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHAF2 p.Arg33= (c.99C>T)?

SDHAF2 p.Arg33= (c.99C>T) is associated with hereditary pheochromocytoma-paraganglioma, hereditary neoplastic syndrome (ClinVar).

How common is SDHAF2 p.Arg33= (c.99C>T) in the general population?

SDHAF2 p.Arg33= (c.99C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SDHAF2 p.Arg33=

c.99C>T · rs753325226 · VCV1147320

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Conditions

hereditary pheochromocytoma-paraganglioma

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 -1.2	GERP -2
Overall
CADD	13.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,088 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.000991% 16/1,614,210 alleles · ultra-rare exomes 16/1,461,884 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,073
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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: SDHAF2
Protein: p.Arg33=
Coding: c.99C>T
MANE Select: NM_017841
dbSNP: rs753325226
Type: single nucleotide variant
Location: chr11:61437687 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 2 PDB

Full SDHAF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHAF2 p.Arg33His Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Arg33Leu Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Arg33Cys Benign/Likely benign ★★ same residue
SDHAF2 p.Arg33Pro Uncertain significance ★ ⚠ same residue
SDHAF2 c.260+1G>A Likely pathogenic ★★ same condition
SDHAF2 c.261-2A>G Likely pathogenic ★★ same condition
SDHAF2 c.261-2A>T Likely pathogenic ★★ same condition
SDHAF2 c.37-1G>C Pathogenic/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/sdhaf2-p-arg33 (accessed [today's date]).

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