Is SDHB p.Asp48Val (c.143A>T) pathogenic?

SDHB p.Asp48Val (c.143A>T) is classified Conflicting classifications of pathogenicity in SDHB (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-05-18). AlphaMissense: ambiguous (0.5538); Ultra-rare (popmax 0.0263%, sas); Associated with mitochondrial complex 2 deficiency, nuclear type 4.

What condition is associated with SDHB p.Asp48Val (c.143A>T)?

SDHB p.Asp48Val (c.143A>T) is associated with mitochondrial complex 2 deficiency, nuclear type 4, pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma (ClinVar).

How common is SDHB p.Asp48Val (c.143A>T) in the general population?

SDHB p.Asp48Val (c.143A>T) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about SDHB p.Asp48Val (c.143A>T)?

AlphaMissense predicts ambiguous (score 0.5538) — an in-silico prediction, not a clinical call.

SDHB p.Asp48Val

c.143A>T · rs202101384 · VCV39584

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.5538 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mitochondrial complex 2 deficiency, nuclear type 4

Computational evidence

Protein change
AlphaMissense	0.5538	ambiguous
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -13.86	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	28.6	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 0.0263% South Asian · 24/91,088 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00192% 31/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,795
Middle Eastern	0.0164%	6,082
Admixed American	0.00167%	59,996
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000339%	295,003

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.Asp48Val
Coding: c.143A>T
MANE Select: NM_003000
dbSNP: rs202101384
Type: single nucleotide variant
Location: chr1:17044818 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 48: the 2fe-2s ferredoxin-type domain; a UniProt-annotated variant site (in mc2dn4; decreased succinate dehydrogenase (ubiquinone) activity in homozygous patient cells; decreased protein levels in homozygous patient cells)

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

Disease context

mitochondrial complex 2 deficiency, nuclear type 4 — 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 II deficiency, nuclear type 1

Similar variants

SDHB p.Asp48= Conflicting classifications of pathogenicity ★ same residue
SDHB p.Asp48Asn Uncertain significance ★ ⚠ same residue
SDHB p.Asp48fs 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
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-asp48val (accessed [today's date]).

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