Is SDHB p.Val140Phe (c.418G>T) pathogenic?

SDHB p.Val140Phe (c.418G>T) is classified Pathogenic/Likely pathogenic in SDHB (ClinVar, Multiple submitters, 20 submitters; last evaluated 2025-12-26). AlphaMissense: likely pathogenic (0.9722); Very rare (popmax 0.000593%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHB p.Val140Phe (c.418G>T)?

SDHB p.Val140Phe (c.418G>T) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Val140Phe (c.418G>T) in the general population?

SDHB p.Val140Phe (c.418G>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SDHB p.Val140Phe (c.418G>T)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

SDHB p.Val140Phe

c.418G>T · rs267607032 · VCV18454

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic ✓ concordant with ClinVar
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -15.49	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 3.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	27.6	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 0.000593% European (non-Finnish) · 7/1,180,038 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,050 alleles · very rare

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.Val140Phe
Coding: c.418G>T
MANE Select: NM_003000
dbSNP: rs267607032
Type: single nucleotide variant
Location: chr1:17028605 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB

Full SDHB 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 4 pheochromocytoma gastrointestinal stromal tumor Carney-Stratakis syndrome hereditary pheochromocytoma-paraganglioma mitochondrial complex 2 deficiency, nuclear type 4

Similar variants

SDHB p.Val140Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
SDHB p.Val140Ile Uncertain significance ★ ⚠ same residue
SDHB p.Val140fs Pathogenic ★ 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-val140phe (accessed [today's date]).

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