Is SDHD p.Ser94= (c.282C>G) pathogenic?

SDHD p.Ser94= (c.282C>G) is classified Benign/Likely benign in SDHD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0494%, mid); Associated with Cowden syndrome 3.

What condition is associated with SDHD p.Ser94= (c.282C>G)?

SDHD p.Ser94= (c.282C>G) is associated with Cowden syndrome 3, pheochromocytoma/paraganglioma syndrome 1, pheochromocytoma (ClinVar).

How common is SDHD p.Ser94= (c.282C>G) in the general population?

SDHD p.Ser94= (c.282C>G) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

SDHD p.Ser94=

c.282C>G · rs781182616 · VCV184557

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Conditions

Cowden syndrome 3

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 -0.47	GERP -2.8
Overall
CADD	6.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00304% 49/1,614,046 alleles · ultra-rare exomes 47/1,461,868 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00339%	29,501
Admixed American	0.00167%	59,998
South Asian	0.0011%	91,088

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.Ser94=
Coding: c.282C>G
MANE Select: NM_003002
dbSNP: rs781182616
Type: single nucleotide variant
Location: chr11:112088979 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB
Residue 94: an α-helix

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

Disease context

Cowden syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 1 pheochromocytoma Carney-Stratakis syndrome hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHD p.Ser94Cys Uncertain significance ★★ ⚠ same residue
SDHD p.Ser94Phe Uncertain significance ★★ ⚠ same residue
SDHD p.Ser94Tyr 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-ser94 (accessed [today's date]).

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