Is SDHA p.Pro159= (c.477G>A) pathogenic?

SDHA p.Pro159= (c.477G>A) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). Very rare (popmax 0.00267%, afr); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Pro159= (c.477G>A)?

SDHA p.Pro159= (c.477G>A) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Pro159= (c.477G>A) in the general population?

SDHA p.Pro159= (c.477G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

SDHA p.Pro159=

c.477G>A · rs771741537 · VCV472394

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

pheochromocytoma/paraganglioma syndrome 5

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 -6.6	GERP -3.7
Overall
CADD	1.183	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,008 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000806% 13/1,613,168 alleles · very rare exomes 11/1,460,862 · genomes 2/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,504
South Asian	0.0022%	45,518
Remaining individualsnot grpmax-eligible	0.0016%	62,406
European (non-Finnish)	0.000678%	147,495

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.Pro159=
Coding: c.477G>A
MANE Select: NM_004168
dbSNP: rs771741537
Type: single nucleotide variant
Location: chr5:225903 (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

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.Pro159Leu 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
SDHA c.1260+1G>T Likely pathogenic ★★ same condition
SDHA c.1260+2T>A Likely pathogenic ★★ same condition
SDHA c.1261-1G>A 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-pro159 (accessed [today's date]).

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