Is SDHB p.Ile136Val (c.406A>G) pathogenic?

SDHB p.Ile136Val (c.406A>G) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-10-16). AlphaMissense: likely benign (0.0902); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SDHB p.Ile136Val (c.406A>G)?

SDHB p.Ile136Val (c.406A>G) is associated with hereditary neoplastic syndrome, pheochromocytoma/paraganglioma syndrome 4, ovarian cancer (ClinVar).

How common is SDHB p.Ile136Val (c.406A>G) in the general population?

SDHB p.Ile136Val (c.406A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SDHB p.Ile136Val (c.406A>G)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

SDHB p.Ile136Val

c.406A>G · rs2078004347 · VCV946260

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -4.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	20.3	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 0.00223% East Asian · 1/44,892 alleles

Overall 6.84e-05% 1/1,461,866 alleles · very rare

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.Ile136Val
Coding: c.406A>G
MANE Select: NM_003000
dbSNP: rs2078004347
Type: single nucleotide variant
Location: chr1:17028617 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 136: a β-strand

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 ovarian cancer pheochromocytoma gastrointestinal stromal tumor

Similar variants

SDHB p.Ile136Arg Uncertain significance ★★ ⚠ same residue
SDHB p.Ile136Leu Uncertain significance ★★ ⚠ same residue
SDHB p.Ile136= 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-ile136val (accessed [today's date]).

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