Is SDHC p.Phe18Leu (c.54T>G) pathogenic?

SDHC p.Phe18Leu (c.54T>G) is classified Conflicting classifications of pathogenicity in SDHC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.2484); Ultra-rare (popmax 0.0512%, eas); Associated with gastrointestinal stromal tumor.

What condition is associated with SDHC p.Phe18Leu (c.54T>G)?

SDHC p.Phe18Leu (c.54T>G) is associated with gastrointestinal stromal tumor, pheochromocytoma/paraganglioma syndrome 3, Carney-Stratakis syndrome (ClinVar).

How common is SDHC p.Phe18Leu (c.54T>G) in the general population?

SDHC p.Phe18Leu (c.54T>G) is ultra-rare (popmax 0.0512%, eas) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

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

What do computational predictors say about SDHC p.Phe18Leu (c.54T>G)?

AlphaMissense predicts likely benign (score 0.2484) — an in-silico prediction, not a clinical call.

SDHC p.Phe18Leu

c.54T>G · rs200761743 · VCV232892

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2484 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
AlphaMissense	0.2484	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -4.15	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 -1.7	GERP -3.1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.78 · regional, not allelic
Overall
CADD	3.738	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

Grpmax group 0.0512% East Asian · 22/42,996 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00138% 22/1,593,922 alleles · ultra-rare exomes 20/1,441,592 · genomes 2/152,330 · 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.Phe18Leu
Coding: c.54T>G
MANE Select: NM_003001
dbSNP: rs200761743
Type: single nucleotide variant
Location: chr1:161323647 (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

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

Also linked: pheochromocytoma/paraganglioma syndrome 3 Carney-Stratakis syndrome hereditary neoplastic syndrome 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.Phe18= 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
SDHC c.241+1G>A Likely pathogenic ★★ same condition
SDHC c.405+1G>A 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-phe18leu (accessed [today's date]).

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