Is SDHB p.Cys93Phe (c.278G>T) pathogenic?

SDHB p.Cys93Phe (c.278G>T) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SDHB p.Cys93Phe (c.278G>T)?

SDHB p.Cys93Phe (c.278G>T) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Cys93Phe (c.278G>T) in the general population?

SDHB p.Cys93Phe (c.278G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SDHB p.Cys93Phe (c.278G>T)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

SDHB p.Cys93Phe

c.278G>T · rs1131691054 · VCV428924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 4% in SDHB
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -14.77	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	31.0	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

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.Cys93Phe
Coding: c.278G>T
MANE Select: NM_003000
dbSNP: rs1131691054
Type: single nucleotide variant
Location: chr1:17033068 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 93: the 2fe-2s ferredoxin-type domain; a binding site

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

Similar variants

SDHB p.Cys93Arg Pathogenic/Likely pathogenic ★★ same residue
SDHB p.Cys93Tyr Pathogenic/Likely pathogenic ★★ same residue
SDHB p.Cys93= Benign/Likely benign ★★ same residue
SDHB p.Cys93Ter 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

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-cys93phe (accessed [today's date]).

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