Is SDHC p.Ser163= (c.489T>C) pathogenic?

SDHC p.Ser163= (c.489T>C) is classified Benign/Likely benign in SDHC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00892%, eas); Associated with pheochromocytoma/paraganglioma syndrome 3.

What condition is associated with SDHC p.Ser163= (c.489T>C)?

SDHC p.Ser163= (c.489T>C) is associated with pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor, hereditary neoplastic syndrome (ClinVar).

How common is SDHC p.Ser163= (c.489T>C) in the general population?

SDHC p.Ser163= (c.489T>C) is very rare (popmax 0.00892%, eas) (gnomAD).

SDHC p.Ser163=

c.489T>C · rs559747670 · VCV293319

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

pheochromocytoma/paraganglioma syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.24	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP 0.4
Overall
CADD	7.259	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,864 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,613,598 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ser163=
Coding: c.489T>C
MANE Select: NM_003001
dbSNP: rs559747670
Type: single nucleotide variant
Location: chr1:161362412 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB
Residue 163: an α-helix

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

Disease context

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

Also linked: gastrointestinal stromal tumor hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

Similar variants

SDHC p.Ser163Cys Uncertain significance ★★ ⚠ same residue
SDHC p.Ser163Pro Uncertain significance ★★ ⚠ same residue
SDHC p.Ser163Tyr Uncertain significance ★ ⚠ same residue
SDHC p.Ser163Phe 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

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-ser163 (accessed [today's date]).

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