Is SDHB p.Pro197Arg (c.590C>G) pathogenic?

SDHB p.Pro197Arg (c.590C>G) is classified Pathogenic/Likely pathogenic in SDHB (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 0.00102%, nfe); Associated with pheochromocytoma/paraganglioma syndrome 4.

What condition is associated with SDHB p.Pro197Arg (c.590C>G)?

SDHB p.Pro197Arg (c.590C>G) is associated with pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Pro197Arg (c.590C>G) in the general population?

SDHB p.Pro197Arg (c.590C>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about SDHB p.Pro197Arg (c.590C>G)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

SDHB p.Pro197Arg

c.590C>G · rs74315367 · VCV12779

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pheochromocytoma/paraganglioma syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic ✓ concordant with ClinVar
REVEL	0.991	strongly pathogenic-leaning
SaProt	LLR -17.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,970 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,664 alleles · very rare

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: SDHB
Protein: p.Pro197Arg
Coding: c.590C>G
MANE Select: NM_003000
dbSNP: rs74315367
Type: single nucleotide variant
Location: chr1:17024025 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 197: the 4fe-4s ferredoxin-type domain; the 'interaction with sdhaf1' region; a UniProt-annotated variant site (in ppgl4); an α-helix

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

Disease context

pheochromocytoma/paraganglioma syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma gastrointestinal stromal tumor hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHB p.Pro197Ser Likely pathogenic ★★ same residue
SDHB p.Pro197Leu Uncertain significance ★ ⚠ same residue
SDHB p.Pro197= Likely benign ★ same residue
SDHB c.200+1G>A Pathogenic ★★ same condition
SDHB c.200+1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.200+5G>T Likely pathogenic ★★ same condition
SDHB c.201-1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.201-2A>C 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/sdhb-p-pro197arg (accessed [today's date]).

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