Is SDHB p.Met58Val (c.172A>G) pathogenic?

SDHB p.Met58Val (c.172A>G) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1073); Very rare (popmax 0.00415%, nfe); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHB p.Met58Val (c.172A>G)?

SDHB p.Met58Val (c.172A>G) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Met58Val (c.172A>G) in the general population?

SDHB p.Met58Val (c.172A>G) is very rare (popmax 0.00415%, nfe) (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

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

What do computational predictors say about SDHB p.Met58Val (c.172A>G)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

SDHB p.Met58Val

c.172A>G · rs1201188410 · VCV459138

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.683	pathogenic-leaning
SaProt	LLR -7.74	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	22.5	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 0.00415% European (non-Finnish) · 49/1,180,006 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00316% 51/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,940

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: SDHB
Protein: p.Met58Val
Coding: c.172A>G
MANE Select: NM_003000
dbSNP: rs1201188410
Type: single nucleotide variant
Location: chr1:17044789 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 58: the 2fe-2s ferredoxin-type domain; a β-strand

Full SDHB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 4 pheochromocytoma gastrointestinal stromal tumor hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

SDHB p.Met58Ile Uncertain significance ★ same residue
SDHB c.200+1G>A Pathogenic ★★ same condition
SDHB c.200+1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.200+5G>T Likely pathogenic ★★ same condition
SDHB c.201-1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.201-2A>C Pathogenic ★★ same condition
SDHB c.286+1G>A Pathogenic ★★ same condition
SDHB c.286+2T>A 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/sdhb-p-met58val (accessed [today's date]).

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