Is SDHB p.Ser222Pro (c.664T>C) pathogenic?

SDHB p.Ser222Pro (c.664T>C) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-17). AlphaMissense: likely pathogenic (0.8887); Absent from gnomAD v4.1; Associated with pheochromocytoma.

What condition is associated with SDHB p.Ser222Pro (c.664T>C)?

SDHB p.Ser222Pro (c.664T>C) is associated with pheochromocytoma, pheochromocytoma/paraganglioma syndrome 4, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Ser222Pro (c.664T>C) in the general population?

SDHB p.Ser222Pro (c.664T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHB p.Ser222Pro (c.664T>C)?

AlphaMissense predicts likely pathogenic (score 0.8887) — an in-silico prediction, not a clinical call.

SDHB p.Ser222Pro

c.664T>C · rs2101513953 · VCV2943055

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8887 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.8887	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -13.92	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 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	32.0	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

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.Ser222Pro
Coding: c.664T>C
MANE Select: NM_003000
dbSNP: rs2101513953
Type: single nucleotide variant
Location: chr1:17022709 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

SDHB p.Ser222Ala Uncertain significance ★★ ⚠ same residue
SDHB p.Ser222Phe Uncertain significance ★ ⚠ same residue
SDHB p.Ser222= Likely 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
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-ser222pro (accessed [today's date]).

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