Is SDHB p.Asp181Asn (c.541G>A) pathogenic?

SDHB p.Asp181Asn (c.541G>A) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.00223%, eas); Associated with gastrointestinal stromal tumor.

What condition is associated with SDHB p.Asp181Asn (c.541G>A)?

SDHB p.Asp181Asn (c.541G>A) is associated with gastrointestinal stromal tumor, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Asp181Asn (c.541G>A) in the general population?

SDHB p.Asp181Asn (c.541G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Gastrointestinal stromal tumor inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SDHB p.Asp181Asn (c.541G>A)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

SDHB p.Asp181Asn

c.541G>A · rs201385062 · VCV412479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

gastrointestinal stromal tumor

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.704	pathogenic-leaning
SaProt	LLR -10.24	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 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	27.9	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 · 1/44,878 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000435% 7/1,609,704 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.00051%	196,177

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.Asp181Asn
Coding: c.541G>A
MANE Select: NM_003000
dbSNP: rs201385062
Type: single nucleotide variant
Location: chr1:17024074 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 181: the 4fe-4s ferredoxin-type domain; the 'interaction with sdhaf1' region; a turn

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

Disease context

gastrointestinal stromal tumor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma/paraganglioma syndrome 4 pheochromocytoma hereditary neoplastic syndrome hereditary pheochromocytoma-paraganglioma

For Gastrointestinal stromal tumor (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SDHB p.Asp181Glu Uncertain significance ★★ ⚠ same residue
SDHB p.Asp181Gly Uncertain significance ★★ ⚠ same residue
SDHB p.Asp181= Benign/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
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-asp181asn (accessed [today's date]).

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