Is SDHD p.His145= (c.435C>T) pathogenic?

SDHD p.His145= (c.435C>T) is classified Benign/Likely benign in SDHD (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0225%, mid); Associated with pheochromocytoma/paraganglioma syndrome 1.

What condition is associated with SDHD p.His145= (c.435C>T)?

SDHD p.His145= (c.435C>T) is associated with pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma, Carney-Stratakis syndrome (ClinVar).

How common is SDHD p.His145= (c.435C>T) in the general population?

SDHD p.His145= (c.435C>T) is ultra-rare (popmax 0.0225%, mid) (gnomAD).

SDHD p.His145=

c.435C>T · rs200062830 · VCV465239

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, mid)

Conditions

pheochromocytoma/paraganglioma syndrome 1

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 -4.1	GERP -4.3
Overall
CADD	4.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0225% Middle Eastern · 1/4,450 alleles

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

Overall 0.000807% 13/1,610,950 alleles · ultra-rare exomes 10/1,458,740 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0225%	4,450
East Asian	0.00446%	22,444
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
African / African-American	0.00267%	37,424
South Asian	0.0011%	90,972
European (non-Finnish)	0.000509%	196,498

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.His145=
Coding: c.435C>T
MANE Select: NM_003002
dbSNP: rs200062830
Type: single nucleotide variant
Location: chr11:112094925 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 145: a UniProt-annotated variant site (found in an individual with features of cowden syndrome; uncertain significance; increased manganese superoxide dismutase expression and normal reactive oxygen species; no change in akt expression but a 1.2-fold increase of mapk expression); an α-helix

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

Disease context

pheochromocytoma/paraganglioma syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

SDHD p.His145Asn Uncertain significance ★★ ⚠ same residue
SDHD p.His145Gln Uncertain significance ★ ⚠ same residue
SDHD p.His145Tyr Uncertain significance ★ ⚠ 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-his145 (accessed [today's date]).

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