Is SDHD p.Pro87Ser (c.259C>T) pathogenic?

SDHD p.Pro87Ser (c.259C>T) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). AlphaMissense: ambiguous (0.3413); Very rare (popmax 0.0011%, sas); Associated with pheochromocytoma.

What condition is associated with SDHD p.Pro87Ser (c.259C>T)?

SDHD p.Pro87Ser (c.259C>T) is associated with pheochromocytoma, Carney-Stratakis syndrome, Cowden syndrome 3 (ClinVar).

How common is SDHD p.Pro87Ser (c.259C>T) in the general population?

SDHD p.Pro87Ser (c.259C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SDHD p.Pro87Ser (c.259C>T)?

AlphaMissense predicts ambiguous (score 0.3413) — an in-silico prediction, not a clinical call.

SDHD p.Pro87Ser

c.259C>T · rs1279566824 · VCV947286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.3413	ambiguous
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -9.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	27.2	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

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 0.000124% 2/1,614,100 alleles · very rare exomes 2/1,461,812 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,013

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.Pro87Ser
Coding: c.259C>T
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

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

Also linked: Carney-Stratakis syndrome Cowden syndrome 3 hereditary neoplastic syndrome

Similar variants

SDHD p.Pro87Thr Uncertain significance ★★ ⚠ same residue
SDHD p.Pro87Ala Uncertain significance ★ ⚠ same residue
SDHD p.Pro87Arg Uncertain significance ★ ⚠ same residue
SDHD p.Pro87His Uncertain significance ★ ⚠ same residue
SDHD p.Pro87Leu Uncertain significance ★ ⚠ same residue
SDHD p.Pro87= Likely benign ★ 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-pro87ser (accessed [today's date]).

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