Is SDHA p.Val528= (c.1584G>A) pathogenic?

SDHA p.Val528= (c.1584G>A) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-15). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Val528= (c.1584G>A)?

SDHA p.Val528= (c.1584G>A) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 5, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Val528= (c.1584G>A) in the general population?

SDHA p.Val528= (c.1584G>A) is absent from gnomAD v4.1 (gnomAD).

SDHA p.Val528=

c.1584G>A · rs2477454615 · VCV1775774

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.67	acceptor gain · deltas
Pangolin	Δ0.50	gain · loss 0.37 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.4	GERP 0.61, phastCons 1
Overall
CADD	18.97	PHRED · no single calibrated threshold — expert panels disagree

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.Val528=
Coding: c.1584G>A
MANE Select: NM_004168
dbSNP: rs2477454615
Type: single nucleotide variant
Location: chr5:251024 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

SDHA p.Val528Met Uncertain significance ★★ ⚠ 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
SDHA c.1260+1G>T Likely pathogenic ★★ same condition
SDHA c.1260+2T>A Likely pathogenic ★★ same condition
SDHA c.1261-1G>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-val528 (accessed [today's date]).

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