Is SDHC p.Ser88= (c.264G>A) pathogenic?

SDHC p.Ser88= (c.264G>A) is classified Conflicting classifications of pathogenicity in SDHC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-09). Very rare (popmax 0.00333%, amr); Associated with gastrointestinal stromal tumor.

What condition is associated with SDHC p.Ser88= (c.264G>A)?

SDHC p.Ser88= (c.264G>A) is associated with gastrointestinal stromal tumor, pheochromocytoma/paraganglioma syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is SDHC p.Ser88= (c.264G>A) in the general population?

SDHC p.Ser88= (c.264G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

SDHC p.Ser88=

c.264G>A · rs1277488324 · VCV465969

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

gastrointestinal stromal tumor

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 -3.1
Overall
CADD	2.997	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00186% 30/1,613,678 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,985
Remaining individualsnot grpmax-eligible	0.0032%	31,233
European (non-Finnish)	0.00212%	47,194
African / African-American	0.00134%	74,840

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: SDHC
Protein: p.Ser88=
Coding: c.264G>A
MANE Select: NM_003001
dbSNP: rs1277488324
Type: single nucleotide variant
Location: chr1:161356699 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB
Residue 88: an α-helix

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

Disease context

gastrointestinal stromal tumor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 3 hereditary neoplastic syndrome Cowden disease hereditary pheochromocytoma-paraganglioma

For Gastrointestinal stromal tumor (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SDHC p.Ser88Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHC p.Ser88Trp Uncertain significance ★ ⚠ same residue
SDHC c.179+1G>C Likely pathogenic ★★ same condition
SDHC c.179+1G>T Likely pathogenic ★★ same condition
SDHC c.180-2A>G Likely pathogenic ★★ same condition
SDHC c.20+1G>T Likely pathogenic ★★ same condition
SDHC c.21-2A>G Pathogenic/Likely pathogenic ★★ same condition
SDHC c.241+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/sdhc-p-ser88 (accessed [today's date]).

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