Is SDHC p.Pro20Ser (c.58C>T) pathogenic?

SDHC p.Pro20Ser (c.58C>T) is classified Uncertain significance in SDHC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.0771); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHC p.Pro20Ser (c.58C>T)?

SDHC p.Pro20Ser (c.58C>T) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor (ClinVar).

How common is SDHC p.Pro20Ser (c.58C>T) in the general population?

SDHC p.Pro20Ser (c.58C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SDHC p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

SDHC p.Pro20Ser

c.58C>T · rs757465324 · VCV2493307

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.55, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.78 · regional, not allelic
Overall
CADD	17.07	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 0.000254% European (non-Finnish) · 3/1,178,848 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,646 alleles · very rare exomes 3/1,460,410 · genomes 0/152,236 · joint denominator

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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_003001
dbSNP: rs757465324
Type: single nucleotide variant
Location: chr1:161323651 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB

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

Disease context

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

Also linked: pheochromocytoma/paraganglioma syndrome 3 gastrointestinal stromal tumor

Similar variants

SDHC p.Pro20Arg Uncertain significance ★★ ⚠ same residue
SDHC p.Pro20Ala Uncertain significance ★ ⚠ same residue
SDHC p.Pro20= Likely benign ★ 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

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-pro20ser (accessed [today's date]).

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