Is SDHB p.Lys123= (c.369G>A) pathogenic?

SDHB p.Lys123= (c.369G>A) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-12). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHB p.Lys123= (c.369G>A)?

SDHB p.Lys123= (c.369G>A) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Lys123= (c.369G>A) in the general population?

SDHB p.Lys123= (c.369G>A) is absent from gnomAD v4.1 (gnomAD).

SDHB p.Lys123=

c.369G>A · rs2101523108 · VCV1734041

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.34	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP -2.4, phastCons 1
Overall
CADD	16.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SDHB
Protein: p.Lys123=
Coding: c.369G>A
MANE Select: NM_003000
dbSNP: rs2101523108
Type: single nucleotide variant
Location: chr1:17028654 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 123: the 2fe-2s ferredoxin-type domain; a β-strand

Full SDHB 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: pheochromocytoma/paraganglioma syndrome 4 pheochromocytoma gastrointestinal stromal tumor

Similar variants

SDHB p.Lys123Glu Uncertain significance ★★ ⚠ same residue
SDHB p.Lys123Thr Uncertain significance ★★ ⚠ same residue
SDHB p.Lys123Arg 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

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-lys123 (accessed [today's date]).

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