Is SDHB p.Met103Val (c.307A>G) pathogenic?

SDHB p.Met103Val (c.307A>G) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.3629); Ultra-rare (popmax 0.0717%, amr); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHB p.Met103Val (c.307A>G)?

SDHB p.Met103Val (c.307A>G) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Met103Val (c.307A>G) in the general population?

SDHB p.Met103Val (c.307A>G) is ultra-rare (popmax 0.0717%, amr) (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.Met103Val (c.307A>G)?

AlphaMissense predicts ambiguous (score 0.3629) — an in-silico prediction, not a clinical call.

SDHB p.Met103Val

c.307A>G · rs140178341 · VCV239429

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.3629	ambiguous
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -14.25	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	26.1	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 0.0717% Admixed American · 43/60,002 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00508% 82/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0717%	1,395
East Asian	0.00668%	14,967
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.00439%	22,772
European (non-Finnish)	0.00237%	42,144
Finnishnot grpmax-eligible	0.00156%	63,992

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: SDHB
Protein: p.Met103Val
Coding: c.307A>G
MANE Select: NM_003000
dbSNP: rs140178341
Type: single nucleotide variant
Location: chr1:17028716 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 103: the 2fe-2s ferredoxin-type domain; a UniProt-annotated variant site (in mc2dn4); 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 Carney-Stratakis syndrome hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

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

Similar variants

SDHB p.Met103Thr Uncertain significance ★★ ⚠ same residue
SDHB p.Met103Arg Likely pathogenic ★ ⚠ same residue
SDHB p.Met103Ile 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

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-met103val (accessed [today's date]).

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