Is SDHA p.Ala338Pro (c.1012G>C) pathogenic?

SDHA p.Ala338Pro (c.1012G>C) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1; Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Ala338Pro (c.1012G>C)?

SDHA p.Ala338Pro (c.1012G>C) is associated with mitochondrial complex II deficiency, nuclear type 1, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Ala338Pro (c.1012G>C) in the general population?

SDHA p.Ala338Pro (c.1012G>C) is absent from gnomAD v4.1 (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.Ala338Pro (c.1012G>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

SDHA p.Ala338Pro

c.1012G>C · rs2126577878 · VCV1734538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex II deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 10% in SDHA
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -14.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	27.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SDHA
Protein: p.Ala338Pro
Coding: c.1012G>C
MANE Select: NM_004168
dbSNP: rs2126577878
Type: single nucleotide variant
Location: chr5:233593 (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: pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome

For Isolated succinate-CoQ reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SDHA p.Ala338Thr Uncertain significance ★★ ⚠ same residue
SDHA p.Ala338Val Uncertain significance ★★ ⚠ same residue
SDHA p.Ala338= Likely benign ★★ same residue
SDHA p.Ala338Gly Uncertain significance ★ ⚠ same residue
SDHA p.Ala338fs 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-ala338pro (accessed [today's date]).

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