Is SDHD p.Pro87Thr (c.259C>A) pathogenic?

SDHD p.Pro87Thr (c.259C>A) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-11). AlphaMissense: ambiguous (0.3562); Absent from gnomAD v4.1; Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHD p.Pro87Thr (c.259C>A)?

SDHD p.Pro87Thr (c.259C>A) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.Pro87Thr (c.259C>A) in the general population?

SDHD p.Pro87Thr (c.259C>A) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

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

What do computational predictors say about SDHD p.Pro87Thr (c.259C>A)?

AlphaMissense predicts ambiguous (score 0.3562) — an in-silico prediction, not a clinical call.

SDHD p.Pro87Thr

c.259C>A · rs1279566824 · VCV3075083

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3562 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.3562	ambiguous
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -10.54	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	26.9	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

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: SDHD
Protein: p.Pro87Thr
Coding: c.259C>A
MANE Select: NM_003002
dbSNP: rs1279566824
Type: single nucleotide variant
Location: chr11:112088956 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB

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 Carney-Stratakis syndrome Cowden syndrome 3

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

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

Similar variants

SDHD p.Pro87Ser Uncertain significance ★★ ⚠ same residue
SDHD p.Pro87His Uncertain significance ★ ⚠ same residue
SDHD p.Pro87= Likely benign ★ same residue
SDHD p.Pro87Ala Uncertain significance ★ ⚠ same residue
SDHD p.Pro87Arg Uncertain significance ★ ⚠ same residue
SDHD p.Pro87Leu Uncertain significance ★ ⚠ same residue
SDHD c.170-1G>T Pathogenic ★★ same condition
SDHD c.170-2A>G 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-pro87thr (accessed [today's date]).

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