Is SDHB p.Ser152Phe (c.455C>T) pathogenic?

SDHB p.Ser152Phe (c.455C>T) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.4196); Ultra-rare (popmax 0.0468%, afr); Associated with Carney-Stratakis syndrome.

What condition is associated with SDHB p.Ser152Phe (c.455C>T)?

SDHB p.Ser152Phe (c.455C>T) is associated with Carney-Stratakis syndrome, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Ser152Phe (c.455C>T) in the general population?

SDHB p.Ser152Phe (c.455C>T) is ultra-rare (popmax 0.0468%, afr) (gnomAD).

How is Carney-Stratakis syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHB p.Ser152Phe (c.455C>T)?

AlphaMissense predicts ambiguous (score 0.4196) — an in-silico prediction, not a clinical call.

SDHB p.Ser152Phe

c.455C>T · rs200414835 · VCV412492

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4196 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Carney-Stratakis syndrome

Computational evidence

Protein change
AlphaMissense	0.4196	ambiguous
REVEL	0.766	pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	24.7	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 0.0468% African / African-American · 35/74,850 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.00248% 40/1,611,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0468%	2,139
Remaining individualsnot grpmax-eligible	0.00801%	12,485

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.Ser152Phe
Coding: c.455C>T
MANE Select: NM_003000
dbSNP: rs200414835
Type: single nucleotide variant
Location: chr1:17027834 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 152: the 'interaction with sdhaf1' region; an α-helix

Full SDHB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Carney-Stratakis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 4 pheochromocytoma gastrointestinal stromal tumor hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma mitochondrial complex 2 deficiency, nuclear type 4

For Carney-Stratakis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

SDHB p.Ser152= Benign/Likely benign ★★ same residue
SDHB p.Ser152Pro Uncertain significance ★ ⚠ same residue
SDHB p.Ser152Tyr 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

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-ser152phe (accessed [today's date]).

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