Is SDHB p.Pro70Ser (c.208C>T) pathogenic?

SDHB p.Pro70Ser (c.208C>T) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). AlphaMissense: ambiguous (0.3889); Very rare (popmax 6.85e-05%); Associated with pheochromocytoma.

What condition is associated with SDHB p.Pro70Ser (c.208C>T)?

SDHB p.Pro70Ser (c.208C>T) is associated with pheochromocytoma, pheochromocytoma/paraganglioma syndrome 4, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Pro70Ser (c.208C>T) in the general population?

SDHB p.Pro70Ser (c.208C>T) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about SDHB p.Pro70Ser (c.208C>T)?

AlphaMissense predicts ambiguous (score 0.3889) — an in-silico prediction, not a clinical call.

SDHB p.Pro70Ser

c.208C>T · rs200890320 · VCV1403368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.3889	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -13.54	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	24.4	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 6.85e-05%

Overall 6.85e-05% 1/1,459,304 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.Pro70Ser
Coding: c.208C>T
MANE Select: NM_003000
dbSNP: rs200890320
Type: single nucleotide variant
Location: chr1:17033138 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 70: the 2fe-2s ferredoxin-type domain

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

Disease context

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

Also linked: pheochromocytoma/paraganglioma syndrome 4 gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

SDHB p.Pro70Thr Uncertain significance ★★ ⚠ same residue
SDHB p.Pro70Ala Uncertain significance ★ ⚠ 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
SDHB c.286+1G>A 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-pro70ser (accessed [today's date]).

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