Is SDHD p.Val46fs (c.136_143del) pathogenic?

SDHD p.Val46fs (c.136143del) is classified Pathogenic in SDHD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). Very rare (popmax 0.00017%, nfe); Associated with Carney-Stratakis syndrome.

What condition is associated with SDHD p.Val46fs (c.136_143del)?

SDHD p.Val46fs (c.136_143del) is associated with Carney-Stratakis syndrome, pheochromocytoma, Cowden syndrome 3 (ClinVar).

How common is SDHD p.Val46fs (c.136_143del) in the general population?

SDHD p.Val46fs (c.136_143del) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Carney-Stratakis syndrome inherited?

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

SDHD p.Val46fs

c.136_143del · rs2498900155 · VCV2035265

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Carney-Stratakis syndrome

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	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 1.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,996 alleles · very rare exomes 2/1,460,744 · genomes 0/152,252 · 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: SDHD
Protein: p.Val46fs
Coding: c.136_143del
MANE Select: NM_003002
dbSNP: rs2498900155
Type: Deletion
Location: chr11:112087939 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.50 · 2 PDB

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

Disease context

Carney-Stratakis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma Cowden syndrome 3

For Carney-Stratakis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

SDHD p.Val46Leu Uncertain significance ★★ ⚠ same residue
SDHD p.Val46Met Uncertain significance ★★ ⚠ same residue
SDHD p.Val46= Benign/Likely benign ★★ same residue
SDHD p.Gln109fs Pathogenic ★★ same condition
SDHD p.Gly58fs Pathogenic ★★ same condition
SDHD p.Leu128fs Pathogenic ★★ same condition
SDHD p.Leu20fs Pathogenic ★★ same condition
SDHD p.Pro81fs 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/sdhd-p-val46fs (accessed [today's date]).

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