Is SDHA p.Val557= (c.1671C>A) pathogenic?

SDHA p.Val557= (c.1671C>A) is classified Benign/Likely benign in SDHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-08). Ultra-rare (popmax 0.0245%, eas); Associated with pheochromocytoma/paraganglioma syndrome 5.

What condition is associated with SDHA p.Val557= (c.1671C>A)?

SDHA p.Val557= (c.1671C>A) is associated with pheochromocytoma/paraganglioma syndrome 5, hereditary neoplastic syndrome, mitochondrial complex II deficiency, nuclear type 1 (ClinVar).

How common is SDHA p.Val557= (c.1671C>A) in the general population?

SDHA p.Val557= (c.1671C>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

SDHA p.Val557=

c.1671C>A · rs767963713 · VCV1136372

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Conditions

pheochromocytoma/paraganglioma syndrome 5

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 -0.12	GERP -1.1, phastCons 0.57
Overall
CADD	8.993	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,874 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000744% 12/1,613,224 alleles · ultra-rare exomes 12/1,460,986 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
European (non-Finnish)	8.48e-05%	1,179,654

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.Val557=
Coding: c.1671C>A
MANE Select: NM_004168
dbSNP: rs767963713
Type: single nucleotide variant
Location: chr5:251345 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 5 PDB
Residue 557: 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.Val557Ile Uncertain significance ★★ ⚠ same residue
SDHA p.Val557Ala Uncertain significance ★ ⚠ same residue
SDHA p.Val557Phe 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-val557 (accessed [today's date]).

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