Is SDHB p.Pro49Ser (c.145C>T) pathogenic?

SDHB p.Pro49Ser (c.145C>T) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-09). AlphaMissense: likely pathogenic (0.569); Very rare (popmax 0.00167%, amr); Associated with pheochromocytoma.

What condition is associated with SDHB p.Pro49Ser (c.145C>T)?

SDHB p.Pro49Ser (c.145C>T) is associated with pheochromocytoma, pheochromocytoma/paraganglioma syndrome 4, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Pro49Ser (c.145C>T) in the general population?

SDHB p.Pro49Ser (c.145C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SDHB p.Pro49Ser (c.145C>T)?

AlphaMissense predicts likely pathogenic (score 0.569) — an in-silico prediction, not a clinical call.

SDHB p.Pro49Ser

c.145C>T · rs2078100145 · VCV2939463

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pheochromocytoma

Computational evidence

Protein change
AlphaMissense	0.569	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -11.18	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.00167% Admixed American · 1/59,998 alleles

Overall 0.000248% 4/1,613,926 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,894
European (non-Finnish)	8.47e-05%	1,179,986

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.Pro49Ser
Coding: c.145C>T
MANE Select: NM_003000
dbSNP: rs2078100145
Type: single nucleotide variant
Location: chr1:17044816 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 49: the 2fe-2s ferredoxin-type domain; a β-strand

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.Pro49Leu Uncertain significance ★★ ⚠ same residue
SDHB p.Pro49Gln Uncertain significance ★ ⚠ same residue
SDHB p.Pro49= Likely benign ★ same residue
SDHB p.Pro49fs 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-pro49ser (accessed [today's date]).

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