Is SDHAF2 p.Phe89fs (c.267del) pathogenic?

SDHAF2 p.Phe89fs (c.267del) is classified Pathogenic/Likely pathogenic in SDHAF2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-20). Very rare (popmax 0.00134%, afr); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHAF2 p.Phe89fs (c.267del)?

SDHAF2 p.Phe89fs (c.267del) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is SDHAF2 p.Phe89fs (c.267del) in the general population?

SDHAF2 p.Phe89fs (c.267del) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

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

SDHAF2 p.Phe89fs

c.267del · rs766035180 · VCV1451128

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(T)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,758 alleles

Overall 0.000124% 2/1,613,388 alleles · very rare exomes 2/1,461,610 · genomes 0/151,778 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,758
European (non-Finnish)	8.48e-05%	1,179,743

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.Phe89fs
Coding: c.267del
MANE Select: NM_017841
dbSNP: rs766035180
Type: Deletion
Location: chr11:61438006 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 2 PDB
Residue 89: an α-helix

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: pheochromocytoma/paraganglioma syndrome 2 hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

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

Similar variants

SDHAF2 p.Phe89Leu Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Phe89Val Uncertain significance ★ ⚠ same residue
SDHAF2 p.Phe89= Likely benign ★ same residue
SDHAF2 p.Asp42fs Pathogenic ★★ same condition
SDHAF2 p.Glu99fs Pathogenic/Likely pathogenic ★★ same condition
SDHAF2 p.Leu26fs Pathogenic/Likely pathogenic ★★ same condition
SDHAF2 p.Ser4fs Pathogenic/Likely pathogenic ★★ same condition
SDHAF2 c.366_370+9del Uncertain significance ★★ 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-phe89fs (accessed [today's date]).

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