Is SDHD p.Pro81= (c.243G>C) pathogenic?

SDHD p.Pro81= (c.243G>C) is classified Benign/Likely benign in SDHD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-18). Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHD p.Pro81= (c.243G>C)?

SDHD p.Pro81= (c.243G>C) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Pro81= (c.243G>C) in the general population?

SDHD p.Pro81= (c.243G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

SDHD p.Pro81=

c.243G>C · rs575262156 · VCV486438

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -4.3, phastCons 0.005
Overall
CADD	6.149	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,792 alleles · very rare exomes 4/1,461,516 · genomes 1/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	8.47e-05%	1,179,997

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.Pro81=
Coding: c.243G>C
MANE Select: NM_003002
dbSNP: rs575262156
Type: single nucleotide variant
Location: chr11:112088940 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 81: a UniProt-annotated variant site (in ppgl1); an α-helix

Full SDHD 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 1 pheochromocytoma Carney-Stratakis syndrome Cowden syndrome 3 hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.Pro81Leu Pathogenic/Likely pathogenic ★★ same residue
SDHD p.Pro81Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHD p.Pro81fs 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

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-pro81 (accessed [today's date]).

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