Is SDHD p.His30Pro (c.89A>C) pathogenic?

SDHD p.His30Pro (c.89A>C) is classified Uncertain significance in SDHD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0586); Very rare (popmax 0.00134%, afr); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHD p.His30Pro (c.89A>C)?

SDHD p.His30Pro (c.89A>C) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.His30Pro (c.89A>C) in the general population?

SDHD p.His30Pro (c.89A>C) is very rare (popmax 0.00134%, afr) (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.His30Pro (c.89A>C)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

SDHD p.His30Pro

c.89A>C · rs1592778803 · VCV648612

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4.3
Regional constraint	o/e 0.83	unconstrained · MANE · 8,059 bp · p 0.019 · regional, not allelic
Overall
CADD	0.471	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,878 alleles

Overall 0.000124% 2/1,613,762 alleles · very rare exomes 1/1,461,652 · genomes 1/152,110 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-Americangrpmax	0.00134%	74,878

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His30Pro
Coding: c.89A>C
MANE Select: NM_003002
dbSNP: rs1592778803
Type: single nucleotide variant
Location: chr11:112087893 (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 hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

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

Similar variants

SDHD p.His30Tyr Uncertain significance ★★ ⚠ same residue
SDHD p.His30= Likely benign ★★ same residue
SDHD p.His30Asp Uncertain significance ★ ⚠ same residue
SDHD p.His30Gln Uncertain significance ★ ⚠ same residue
SDHD p.His30fs Pathogenic ★ same residue
SDHD p.His30delinsGlnGln 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-his30pro (accessed [today's date]).

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