Is SDHA p.Ser339Pro (c.1015T>C) pathogenic?

SDHA p.Ser339Pro (c.1015T>C) is classified Conflicting classifications of pathogenicity in SDHA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2020-02-08). AlphaMissense: likely pathogenic (0.8758); Absent from gnomAD v4.1; Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Ser339Pro (c.1015T>C)?

SDHA p.Ser339Pro (c.1015T>C) is associated with pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

How common is SDHA p.Ser339Pro (c.1015T>C) in the general population?

SDHA p.Ser339Pro (c.1015T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHA p.Ser339Pro (c.1015T>C)?

AlphaMissense predicts likely pathogenic (score 0.8758) — an in-silico prediction, not a clinical call.

SDHA p.Ser339Pro

c.1015T>C · rs1553999041 · VCV444647

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8758 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
AlphaMissense	0.8758	likely pathogenic
REVEL	0.691	pathogenic-leaning
SaProt	LLR -11.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	23.2	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.Ser339Pro
Coding: c.1015T>C
MANE Select: NM_004168
dbSNP: rs1553999041
Type: single nucleotide variant
Location: chr5:233596 (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

pheochromocytoma/paraganglioma syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SDHA p.Ser339Cys Uncertain significance ★★ ⚠ same residue
SDHA p.Ser339= Benign/Likely benign ★★ same residue
SDHA p.Ser339Phe 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

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-ser339pro (accessed [today's date]).

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