Is SDHD p.Lys122= (c.366A>G) pathogenic?

SDHD p.Lys122= (c.366A>G) is classified Benign/Likely benign in SDHD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-06). Ultra-rare (popmax 0.0225%, mid); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHD p.Lys122= (c.366A>G)?

SDHD p.Lys122= (c.366A>G) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Lys122= (c.366A>G) in the general population?

SDHD p.Lys122= (c.366A>G) is ultra-rare (popmax 0.0225%, mid) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SDHD p.Lys122=

c.366A>G · rs780764151 · VCV824046

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, mid)

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.364	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.9	GERP -0.19, phastCons 0.98
Overall
CADD	8.852	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0225% Middle Eastern · 1/4,452 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00977%

Overall 0.00136% 22/1,611,898 alleles · ultra-rare exomes 21/1,459,654 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0225%	4,452
South Asian	0.0187%	5,352
Remaining individualsnot grpmax-eligible	0.00642%	15,575

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: SDHD
Protein: p.Lys122=
Coding: c.366A>G
MANE Select: NM_003002
dbSNP: rs780764151
Type: single nucleotide variant
Location: chr11:112094856 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 122: an α-helix

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

Disease context

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

Also linked: pheochromocytoma/paraganglioma syndrome 1 pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3 hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHD p.Lys122Arg Uncertain significance ★★ ⚠ same residue
SDHD p.Lys122Ter Pathogenic ★ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G Pathogenic/Likely pathogenic ★★ same condition
SDHD c.314+1G>A Pathogenic ★★ same condition
SDHD c.314+1G>T Pathogenic ★★ same condition
SDHD c.315-1G>A Likely pathogenic ★★ same condition
SDHD c.315-2A>C Pathogenic/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/sdhd-p-lys122 (accessed [today's date]).

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