Is SDHA p.Pro643Ser (c.1927C>T) pathogenic?

SDHA p.Pro643Ser (c.1927C>T) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-02). AlphaMissense: likely benign (0.1984); Absent from gnomAD v4.1; Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Pro643Ser (c.1927C>T)?

SDHA p.Pro643Ser (c.1927C>T) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Pro643Ser (c.1927C>T) in the general population?

SDHA p.Pro643Ser (c.1927C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHA p.Pro643Ser (c.1927C>T)?

AlphaMissense predicts likely benign (score 0.1984) — an in-silico prediction, not a clinical call.

SDHA p.Pro643Ser

c.1927C>T · rs1579448568 · VCV659942

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pheochromocytoma/paraganglioma syndrome 5

Computational evidence

Protein change
AlphaMissense	0.1984	likely benign
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -11.26	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	24.7	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.Pro643Ser
Coding: c.1927C>T
MANE Select: NM_004168
dbSNP: rs1579448568
Type: single nucleotide variant
Location: chr5:256352 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 643: a β-strand

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

Also linked: hereditary neoplastic syndrome mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Pro643Arg Uncertain significance ★★ ⚠ same residue
SDHA p.Pro643Thr Uncertain significance ★★ ⚠ same residue
SDHA p.Pro643Leu Uncertain significance ★ ⚠ same residue
SDHA p.Pro643= Likely benign ★ same residue
SDHA p.Pro643_Val644= 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

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-pro643ser (accessed [today's date]).

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