Is SP110 p.Arg421Gln (c.1262G>A) pathogenic?

SP110 p.Arg421Gln (c.1262G>A) is classified Conflicting classifications of pathogenicity in SP110 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-07-25). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.016%, afr); Associated with hepatic veno-occlusive disease-immunodeficiency syndrome.

What condition is associated with SP110 p.Arg421Gln (c.1262G>A)?

SP110 p.Arg421Gln (c.1262G>A) is associated with hepatic veno-occlusive disease-immunodeficiency syndrome (ClinVar).

How common is SP110 p.Arg421Gln (c.1262G>A) in the general population?

SP110 p.Arg421Gln (c.1262G>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about SP110 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

SP110 p.Arg421Gln

Q: How is Hepatic veno-occlusive disease-immunodeficiency syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1262G>A · rs140588937 · VCV1055551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hepatic veno-occlusive disease-immunodeficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -2.9
Regional constraint	o/e 0.92	unconstrained · MANE · 48 kb · p 0.016 · regional, not allelic
Overall
CADD	0.02	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 0.016% African / African-American · 12/74,914 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00279% 45/1,613,972 alleles · ultra-rare exomes 31/1,461,800 · genomes 14/152,172 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,243
Admixed American	0.00333%	29,998
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00237%	42,141
South Asian	0.0011%	91,088

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: SP110
Protein: p.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_080424
dbSNP: rs140588937
Type: single nucleotide variant
Location: chr2:230186011 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.63

Full SP110 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hepatic veno-occlusive disease-immunodeficiency syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hepatic veno-occlusive disease-immunodeficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

SP110 p.Arg421Ter Pathogenic/Likely pathogenic ★★ same residue
SP110 c.1888-2A>G Likely pathogenic ★★ same condition
SP110 p.Arg344Ter Pathogenic/Likely pathogenic ★★ same condition
SP110 p.Arg448Ter Pathogenic/Likely pathogenic ★★ same condition
SP110 p.Arg554Ter Pathogenic/Likely pathogenic ★★ same condition
SP110 p.Arg631Ter Pathogenic/Likely pathogenic ★★ same condition
SP110 c.1591-6T>G Uncertain significance ★★ same condition
SP110 c.583+3G>A Uncertain significance ★★ 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/sp110-p-arg421gln (accessed [today's date]).

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