Is SDHB p.Ile136= (c.408A>C) pathogenic?

SDHB p.Ile136= (c.408A>C) is classified Uncertain significance in SDHB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-20). Very rare (popmax 6.84e-05%); Associated with pheochromocytoma.

What condition is associated with SDHB p.Ile136= (c.408A>C)?

SDHB p.Ile136= (c.408A>C) is associated with pheochromocytoma, pheochromocytoma/paraganglioma syndrome 4, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Ile136= (c.408A>C) in the general population?

SDHB p.Ile136= (c.408A>C) is very rare (popmax 6.84e-05%) (gnomAD).

SDHB p.Ile136=

c.408A>C · rs2525020325 · VCV1949983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

pheochromocytoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor loss, 39 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.12	GERP -4.4, phastCons 0.6
Overall
CADD	6.843	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,874 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.Ile136=
Coding: c.408A>C
MANE Select: NM_003000
dbSNP: rs2525020325
Type: single nucleotide variant
Location: chr1:17028615 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 136: a β-strand

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

Similar variants

SDHB p.Ile136Arg Uncertain significance ★★ ⚠ same residue
SDHB p.Ile136Leu Uncertain significance ★★ ⚠ same residue
SDHB p.Ile136Val Conflicting classifications of pathogenicity ★ ⚠ 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-ile136 (accessed [today's date]).

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