Is SDHA p.Pro643Arg (c.1928C>G) pathogenic?

SDHA p.Pro643Arg (c.1928C>G) is classified Uncertain significance in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-02). AlphaMissense: likely benign (0.2792); Very rare (popmax 0.00223%, eas); Associated with dilated cardiomyopathy 1GG.

What condition is associated with SDHA p.Pro643Arg (c.1928C>G)?

SDHA p.Pro643Arg (c.1928C>G) is associated with dilated cardiomyopathy 1GG, pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is SDHA p.Pro643Arg (c.1928C>G) in the general population?

SDHA p.Pro643Arg (c.1928C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHA p.Pro643Arg (c.1928C>G)?

AlphaMissense predicts likely benign (score 0.2792) — an in-silico prediction, not a clinical call.

SDHA p.Pro643Arg

c.1928C>G · rs1060503717 · VCV412372

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1GG

Computational evidence

Protein change
AlphaMissense	0.2792	likely benign
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -14.68	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 1.1e-12 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.00223% East Asian · 1/44,902 alleles

Overall 0.000124% 2/1,613,580 alleles · very rare exomes 1/1,461,422 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,902
Admixed American	0.00167%	59,992

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.Pro643Arg
Coding: c.1928C>G
MANE Select: NM_004168
dbSNP: rs1060503717
Type: single nucleotide variant
Location: chr5:256353 (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

dilated cardiomyopathy 1GG — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 5 hereditary neoplastic syndrome neurodegeneration with ataxia and late-onset optic atrophy mitochondrial complex II deficiency, nuclear type 1

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SDHA p.Pro643Ser 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-pro643arg (accessed [today's date]).

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