Is SDHC p.Pro54Ser (c.160C>T) pathogenic?

SDHC p.Pro54Ser (c.160C>T) is classified Conflicting classifications of pathogenicity in SDHC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.9588); Absent from gnomAD v4.1; Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHC p.Pro54Ser (c.160C>T)?

SDHC p.Pro54Ser (c.160C>T) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 3, gastrointestinal stromal tumor (ClinVar).

How common is SDHC p.Pro54Ser (c.160C>T) in the general population?

SDHC p.Pro54Ser (c.160C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHC p.Pro54Ser (c.160C>T)?

AlphaMissense predicts likely pathogenic (score 0.9588) — an in-silico prediction, not a clinical call.

SDHC p.Pro54Ser

c.160C>T · rs1553262444 · VCV1776361

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9588 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.9588	likely pathogenic · top 5% in SDHC
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -13.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.78 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SDHC
Protein: p.Pro54Ser
Coding: c.160C>T
MANE Select: NM_003001
dbSNP: rs1553262444
Type: single nucleotide variant
Location: chr1:161328478 (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 pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 3 gastrointestinal stromal tumor hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHC p.Pro54Ala Uncertain significance ★ ⚠ same residue
SDHC p.Pro54Leu Uncertain significance ★ ⚠ same residue
SDHC p.Pro54Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHC p.Pro54= 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

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-pro54ser (accessed [today's date]).

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