Is SDHA p.Pro399Ser (c.1195C>T) pathogenic?

SDHA p.Pro399Ser (c.1195C>T) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-11). AlphaMissense: likely pathogenic (0.6433); No allele count reported in gnomAD v4.1 (AN 1,614,080); Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Pro399Ser (c.1195C>T)?

SDHA p.Pro399Ser (c.1195C>T) is associated with mitochondrial complex II deficiency, nuclear type 1, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Pro399Ser (c.1195C>T) in the general population?

SDHA p.Pro399Ser (c.1195C>T) is no allele count reported in gnomAD v4.1 (AN 1,614,080) (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.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely pathogenic (score 0.6433) — an in-silico prediction, not a clinical call.

SDHA p.Pro399Ser

c.1195C>T · rs2126585242 · VCV1465960

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6433 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,080)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex II deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.6433	likely pathogenic
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -11.83	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 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	22.4	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

No allele count reported in gnomAD v4.1 (AN 1,614,080). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SDHA
Protein: p.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_004168
dbSNP: rs2126585242
Type: single nucleotide variant
Location: chr5:235274 (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.Pro399Gln Uncertain significance ★★ ⚠ same residue
SDHA p.Pro399Leu Uncertain significance ★★ ⚠ same residue
SDHA p.Pro399Thr Uncertain significance ★★ ⚠ same residue
SDHA p.Pro399= Benign/Likely benign ★★ 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-pro399ser (accessed [today's date]).

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