Is SDHA p.Ala45Val (c.134C>T) pathogenic?

SDHA p.Ala45Val (c.134C>T) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-13). AlphaMissense: likely benign (0.1805); Very rare (popmax 6.2e-05%); Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Ala45Val (c.134C>T)?

SDHA p.Ala45Val (c.134C>T) is associated with mitochondrial complex II deficiency, nuclear type 1, dilated cardiomyopathy 1GG, pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

How common is SDHA p.Ala45Val (c.134C>T) in the general population?

SDHA p.Ala45Val (c.134C>T) is very rare (popmax 6.2e-05%) (gnomAD).

How is Isolated succinate-CoQ reductase deficiency inherited?

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

What do computational predictors say about SDHA p.Ala45Val (c.134C>T)?

AlphaMissense predicts likely benign (score 0.1805) — an in-silico prediction, not a clinical call.

SDHA p.Ala45Val

c.134C>T · rs1553997190 · VCV486376

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex II deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.1805	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 6.2e-05%

Overall 6.2e-05% 1/1,613,184 alleles · very rare exomes 1/1,460,860 · genomes 0/152,324 · 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.Ala45Val
Coding: c.134C>T
MANE Select: NM_004168
dbSNP: rs1553997190
Type: single nucleotide variant
Location: chr5:223552 (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

mitochondrial complex II deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1GG pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome neurodegeneration with ataxia and late-onset optic atrophy

For Isolated succinate-CoQ reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SDHA p.Ala45Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Ala45Gly Uncertain significance ★ ⚠ same residue
SDHA p.Ala45Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Ala45= Likely benign ★ same residue
SDHA p.Ala45fs 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

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-ala45val (accessed [today's date]).

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