Is SDHA p.Pro332Ser (c.994C>T) pathogenic?

SDHA p.Pro332Ser (c.994C>T) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.853); Ultra-rare (popmax 0.066%, mid); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Pro332Ser (c.994C>T)?

SDHA p.Pro332Ser (c.994C>T) is associated with pheochromocytoma/paraganglioma syndrome 5, sick sinus syndrome 2, autosomal dominant, Leigh syndrome (ClinVar).

How common is SDHA p.Pro332Ser (c.994C>T) in the general population?

SDHA p.Pro332Ser (c.994C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about SDHA p.Pro332Ser (c.994C>T)?

AlphaMissense predicts likely pathogenic (score 0.853) — an in-silico prediction, not a clinical call.

SDHA p.Pro332Ser

c.994C>T · rs373509391 · VCV472424

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
AlphaMissense	0.853	likely pathogenic
REVEL	0.5	indeterminate
SaProt	LLR -14.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000248% 4/1,614,192 alleles · ultra-rare exomes 4/1,461,878 · 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.Pro332Ser
Coding: c.994C>T
MANE Select: NM_004168
dbSNP: rs373509391
Type: single nucleotide variant
Location: chr5:233575 (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

pheochromocytoma/paraganglioma syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sick sinus syndrome 2, autosomal dominant Leigh syndrome dilated cardiomyopathy 1GG hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Pro332Ala Uncertain significance ★★ ⚠ same residue
SDHA p.Pro332= Likely benign ★★ same residue
SDHA p.Pro332Arg Uncertain significance ★ ⚠ same residue
SDHA p.Pro332fs Pathogenic ★★ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+1G>T Likely pathogenic ★★ same condition
SDHA c.1064+2T>A Likely pathogenic ★★ same condition
SDHA c.1065-2A>G 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-pro332ser (accessed [today's date]).

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