Is SDHA p.Pro332fs (c.995_996del) pathogenic?

SDHA p.Pro332fs (c.995996del) is classified Pathogenic in SDHA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Pro332fs (c.995_996del)?

SDHA p.Pro332fs (c.995_996del) is associated with hereditary neoplastic syndrome, dilated cardiomyopathy 1GG, pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

How common is SDHA p.Pro332fs (c.995_996del) in the general population?

SDHA p.Pro332fs (c.995_996del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SDHA p.Pro332fs

c.995_996del · rs1560994766 · VCV575469

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 6.2e-05% 1/1,614,192 alleles · ultra-rare exomes 1/1,461,878 · genomes 0/152,314 · 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: SDHA
Protein: p.Pro332fs
Coding: c.995_996del
MANE Select: NM_004168
dbSNP: rs1560994766
Type: Deletion
Location: chr5:233576 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 332: a turn

Full SDHA 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: dilated cardiomyopathy 1GG pheochromocytoma/paraganglioma syndrome 5 mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Pro332Ala Uncertain significance ★★ ⚠ same residue
SDHA p.Pro332Ser Uncertain significance ★★ ⚠ same residue
SDHA p.Pro332= Likely benign ★★ same residue
SDHA p.Pro332Arg Uncertain significance ★ ⚠ same residue
SDHA c.1432_1432+1del Pathogenic/Likely pathogenic ★★ same condition
SDHA c.457-2_457del Pathogenic/Likely pathogenic ★★ same condition
SDHA c.63+2del Likely pathogenic ★★ same condition
SDHA c.762_770+17del 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/sdha-p-pro332fs (accessed [today's date]).

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