Is SDHA p.Val644= (c.1932G>A) pathogenic?

SDHA p.Val644= (c.1932G>A) is classified Benign in SDHA (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 55.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Val644= (c.1932G>A)?

SDHA p.Val644= (c.1932G>A) is associated with hereditary neoplastic syndrome, Leigh syndrome, pheochromocytoma/paraganglioma syndrome 5 (ClinVar).

SDHA p.Val644=

Q: How common is SDHA p.Val644= (c.1932G>A) in the general population?

SDHA p.Val644= (c.1932G>A) is common (popmax 55.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1932G>A · rs6961 · VCV130278

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 55.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.4
Overall
CADD	0.931	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 55.5% African / African-American · 40,316/72,632 alleles

Filtering AF 55.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 54.9%

Overall 21.7% 280,784/1,294,100 alleles · common exomes 243,916/1,148,872 · genomes 36,868/145,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	55.5%	2
Amishnot grpmax-eligible	32%	3
Admixed American	23.5%	4
Middle Eastern	22.1%	5
Remaining individualsnot grpmax-eligible	21.7%	5
European (non-Finnish)	21.2%	5
Ashkenazi Jewishnot grpmax-eligible	19.3%	5
South Asian	11.1%	9
Finnishnot grpmax-eligible	10.6%	9
East Asian	6.36%	16

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.Val644=
Coding: c.1932G>A
MANE Select: NM_004168
dbSNP: rs6961
Type: single nucleotide variant
Location: chr5:256357 (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: Leigh syndrome pheochromocytoma/paraganglioma syndrome 5 hereditary pheochromocytoma-paraganglioma mitochondrial complex II deficiency, nuclear type 1

Similar variants

SDHA p.Val644Met Uncertain significance ★★ ⚠ same residue
SDHA p.Val644Gly Uncertain significance ★ ⚠ same residue
SDHA p.Val644_Ile645= 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
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-val644 (accessed [today's date]).

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