Is SDHA p.Ala331= (c.993C>T) pathogenic?

SDHA p.Ala331= (c.993C>T) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Very rare (popmax 0.000169%, nfe); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Ala331= (c.993C>T)?

SDHA p.Ala331= (c.993C>T) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Ala331= (c.993C>T) in the general population?

SDHA p.Ala331= (c.993C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

SDHA p.Ala331=

c.993C>T · rs1424925197 · VCV762495

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.55	GERP -3.7, phastCons 0.012
Overall
CADD	6.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,030 alleles

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

Overall 0.000124% 2/1,614,166 alleles · very rare exomes 2/1,461,870 · genomes 0/152,296 · 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.Ala331=
Coding: c.993C>T
MANE Select: NM_004168
dbSNP: rs1424925197
Type: single nucleotide variant
Location: chr5:233574 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB

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: hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Ala331Val Uncertain significance ★★ ⚠ same residue
SDHA p.Ala331Gly Uncertain significance ★ ⚠ same residue
SDHA p.Ala331Ser Uncertain significance ★ ⚠ same residue
SDHA p.Ala331Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Ala331Asn Uncertain significance ★ 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

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-ala331 (accessed [today's date]).

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