Is SDHA p.Arg554Pro (c.1661G>C) pathogenic?

SDHA p.Arg554Pro (c.1661G>C) is classified Uncertain significance in SDHA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely pathogenic (0.9667); Very rare (popmax 0.00223%, eas); Associated with mitochondrial complex II deficiency, nuclear type 1.

What condition is associated with SDHA p.Arg554Pro (c.1661G>C)?

SDHA p.Arg554Pro (c.1661G>C) is associated with mitochondrial complex II deficiency, nuclear type 1, pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

How common is SDHA p.Arg554Pro (c.1661G>C) in the general population?

SDHA p.Arg554Pro (c.1661G>C) is very rare (popmax 0.00223%, eas) (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.Arg554Pro (c.1661G>C)?

AlphaMissense predicts likely pathogenic (score 0.9667) — an in-silico prediction, not a clinical call.

SDHA p.Arg554Pro

c.1661G>C · rs376391115 · VCV2933812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex II deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.9667	likely pathogenic
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -11.73	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 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	28.8	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 0.00223% East Asian · 1/44,878 alleles

Overall 6.21e-05% 1/1,611,472 alleles · very rare exomes 1/1,459,158 · 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.Arg554Pro
Coding: c.1661G>C
MANE Select: NM_004168
dbSNP: rs376391115
Type: single nucleotide variant
Location: chr5:251101 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 554: a UniProt-annotated variant site (in ls)

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

For Isolated succinate-CoQ reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SDHA p.Arg554Trp Likely pathogenic ★★ same residue
SDHA p.Arg554Leu Uncertain significance ★★ ⚠ same residue
SDHA p.Arg554= Benign/Likely benign ★★ same residue
SDHA p.Arg554Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg554pro (accessed [today's date]).

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