Is SDHB p.Phe146Val (c.436T>G) pathogenic?

SDHB p.Phe146Val (c.436T>G) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.8472); Very rare (popmax 0.000125%); Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with SDHB p.Phe146Val (c.436T>G)?

SDHB p.Phe146Val (c.436T>G) is associated with hereditary pheochromocytoma-paraganglioma, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Phe146Val (c.436T>G) in the general population?

SDHB p.Phe146Val (c.436T>G) is very rare (popmax 0.000125%) (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.Phe146Val (c.436T>G)?

AlphaMissense predicts likely pathogenic (score 0.8472) — an in-silico prediction, not a clinical call.

SDHB p.Phe146Val

c.436T>G · rs1553177689 · VCV459147

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000125%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.8472	likely pathogenic
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -14.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000125%

Overall 0.000125% 2/1,602,768 alleles · very rare exomes 2/1,450,466 · genomes 0/152,302 · 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: SDHB
Protein: p.Phe146Val
Coding: c.436T>G
MANE Select: NM_003000
dbSNP: rs1553177689
Type: single nucleotide variant
Location: chr1:17027853 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 146: the 'interaction with sdhaf1' region; an α-helix

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.Phe146Leu Uncertain significance ★★ ⚠ same residue
SDHB p.Phe146Ser 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

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-phe146val (accessed [today's date]).

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