Is SDHAF2 p.Pro129= (c.387A>G) pathogenic?

SDHAF2 p.Pro129= (c.387A>G) is classified Likely benign in SDHAF2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00246%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHAF2 p.Pro129= (c.387A>G)?

SDHAF2 p.Pro129= (c.387A>G) is associated with hereditary neoplastic syndrome, hereditary pheochromocytoma-paraganglioma (ClinVar).

How common is SDHAF2 p.Pro129= (c.387A>G) in the general population?

SDHAF2 p.Pro129= (c.387A>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

SDHAF2 p.Pro129=

c.387A>G · rs770383127 · VCV700766

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

hereditary neoplastic syndrome

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 -3.6
Overall
CADD	6.965	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,040 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,614,216 alleles · very rare exomes 29/1,461,870 · genomes 0/152,346 · joint denominator

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.Pro129=
Coding: c.387A>G
MANE Select: NM_017841
dbSNP: rs770383127
Type: single nucleotide variant
Location: chr11:61445957 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 2 PDB
Residue 129: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pheochromocytoma-paraganglioma

Similar variants

SDHAF2 p.Pro129Ala Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Pro129Ser Uncertain significance ★★ ⚠ same residue
SDHAF2 p.Pro129Arg Uncertain significance ★ ⚠ same residue
SDHAF2 p.Pro129Thr 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-pro129 (accessed [today's date]).

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