Is SDHC p.Val154fs (c.460del) pathogenic?

SDHC p.Val154fs (c.460del) is classified Uncertain significance in SDHC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-22). Very rare (popmax 0.0011%, sas); Associated with gastrointestinal stromal tumor.

What condition is associated with SDHC p.Val154fs (c.460del)?

SDHC p.Val154fs (c.460del) is associated with gastrointestinal stromal tumor, pheochromocytoma/paraganglioma syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is SDHC p.Val154fs (c.460del) in the general population?

SDHC p.Val154fs (c.460del) is very rare (popmax 0.0011%, sas) (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.Val154fs

c.460del · rs786201665 · VCV184753

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.45, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,950 alleles

Overall 6.21e-05% 1/1,611,270 alleles · very rare exomes 1/1,461,470 · genomes 0/149,800 · 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.Val154fs
Coding: c.460del
MANE Select: NM_003001
dbSNP: rs786201665
Type: Deletion
Location: chr1:161362382 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 91.05 · 2 PDB
Residue 154: 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

For Gastrointestinal stromal tumor (Orphanet):

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

Similar variants

SDHC p.Val154Leu Uncertain significance ★★ ⚠ same residue
SDHC p.Val154= Likely benign ★★ same residue
SDHC p.Val154Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHC p.Arg40fs Pathogenic ★★ same condition
SDHC p.His17fs Pathogenic ★★ same condition
SDHC p.Trp61fs Pathogenic ★★ same condition
SDHC c.20+4del Uncertain significance ★★ same condition
SDHC p.Ala111del Uncertain significance ★★ 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-val154fs (accessed [today's date]).

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