Is SDHB p.Val5Ala (c.14T>C) pathogenic?

SDHB p.Val5Ala (c.14T>C) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0544); Absent from gnomAD v4.1; Associated with pheochromocytoma/paraganglioma syndrome 4.

What condition is associated with SDHB p.Val5Ala (c.14T>C)?

SDHB p.Val5Ala (c.14T>C) is associated with pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Val5Ala (c.14T>C) in the general population?

SDHB p.Val5Ala (c.14T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHB p.Val5Ala (c.14T>C)?

AlphaMissense predicts likely benign (score 0.0544) — an in-silico prediction, not a clinical call.

SDHB p.Val5Ala

c.14T>C · rs760565241 · VCV649875

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0544 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pheochromocytoma/paraganglioma syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0544	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -5.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.42, phastCons 0.068
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	13.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SDHB
Protein: p.Val5Ala
Coding: c.14T>C
MANE Select: NM_003000
dbSNP: rs760565241
Type: single nucleotide variant
Location: chr1:17054006 (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

pheochromocytoma/paraganglioma syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma gastrointestinal stromal tumor

Similar variants

SDHB p.Val5Gly Uncertain significance ★★ ⚠ same residue
SDHB p.Val5= Likely benign ★★ same residue
SDHB p.Val5Leu Uncertain significance ★ ⚠ same residue
SDHB p.Val5Phe Uncertain significance ★ ⚠ same residue
SDHB p.Val5_Ala6= Benign ★ 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

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-val5ala (accessed [today's date]).

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