Is SDHA p.Asp646= (c.1938C>T) pathogenic?

SDHA p.Asp646= (c.1938C>T) is classified Likely benign in SDHA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-03). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHA p.Asp646= (c.1938C>T)?

SDHA p.Asp646= (c.1938C>T) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 5, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Asp646= (c.1938C>T) in the general population?

SDHA p.Asp646= (c.1938C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SDHA p.Asp646=

c.1938C>T · rs2477489113 · VCV2931229

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 1.4	GERP -1.7, phastCons 1
Overall
CADD	9.855	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Overall 6.2e-05% 1/1,613,872 alleles · ultra-rare exomes 1/1,461,544 · genomes 0/152,328 · joint denominator

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.Asp646=
Coding: c.1938C>T
MANE Select: NM_004168
dbSNP: rs2477489113
Type: single nucleotide variant
Location: chr5:256363 (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.Asp646Asn 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-asp646 (accessed [today's date]).

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