Is SDHA p.Arg451Ser (c.1351C>A) pathogenic?

SDHA p.Arg451Ser (c.1351C>A) is classified Conflicting classifications of pathogenicity in SDHA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-26). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with SDHA-related disorder.

What condition is associated with SDHA p.Arg451Ser (c.1351C>A)?

SDHA p.Arg451Ser (c.1351C>A) is associated with SDHA-related disorder, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Arg451Ser (c.1351C>A) in the general population?

SDHA p.Arg451Ser (c.1351C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHA p.Arg451Ser (c.1351C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

SDHA p.Arg451Ser

c.1351C>A · rs1553999752 · VCV969346

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SDHA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 2% in SDHA
REVEL	0.69	pathogenic-leaning
SaProt	LLR -15.20	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 2.9	GERP -3.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

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.Arg451Ser
Coding: c.1351C>A
MANE Select: NM_004168
dbSNP: rs1553999752
Type: single nucleotide variant
Location: chr5:236518 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 451: a binding site; a UniProt-annotated variant site (in ndaxoa)

Full SDHA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SDHA-related disorder

Also linked: pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Arg451Pro Uncertain significance ★★ ⚠ same residue
SDHA p.Arg451= Benign/Likely benign ★★ same residue
SDHA p.Arg451Leu Likely pathogenic ★ same residue
SDHA p.Arg451Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Arg451His Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHA p.Arg451Gly Uncertain significance ★ ⚠ same residue
SDHA c.1064+1G>A Likely pathogenic ★★ same condition
SDHA c.1064+1G>T 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-arg451ser (accessed [today's date]).

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