Is SDHB p.Arg12Pro (c.35G>C) pathogenic?

SDHB p.Arg12Pro (c.35G>C) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-23). AlphaMissense: likely benign (0.1234); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHB p.Arg12Pro (c.35G>C)?

SDHB p.Arg12Pro (c.35G>C) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Arg12Pro (c.35G>C) in the general population?

SDHB p.Arg12Pro (c.35G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SDHB p.Arg12Pro (c.35G>C)?

AlphaMissense predicts likely benign (score 0.1234) — an in-silico prediction, not a clinical call.

SDHB p.Arg12Pro

c.35G>C · rs1293365726 · VCV581553

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1234	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -7.52	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 1.6	GERP 0.41, phastCons 0.002
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	17.29	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,724 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,460,740 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,362
European (non-Finnish)grpmax	0.000339%	294,931

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg12Pro
Coding: c.35G>C
MANE Select: NM_003000
dbSNP: rs1293365726
Type: single nucleotide variant
Location: chr1:17053985 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

SDHB p.Arg12Gln Uncertain significance ★★ ⚠ same residue
SDHB p.Arg12Leu Uncertain significance ★★ ⚠ same residue
SDHB p.Arg12Trp Uncertain significance ★★ ⚠ same residue
SDHB p.Arg12Gly Uncertain significance ★ ⚠ same residue
SDHB p.Arg12= 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

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-arg12pro (accessed [today's date]).

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