Is C8A p.Ile441Val (c.1321A>G) pathogenic?

C8A p.Ile441Val (c.1321A>G) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0738); Rare (popmax 0.148%, mid); Associated with type I complement component 8 deficiency.

What condition is associated with C8A p.Ile441Val (c.1321A>G)?

C8A p.Ile441Val (c.1321A>G) is associated with type I complement component 8 deficiency (ClinVar).

How common is C8A p.Ile441Val (c.1321A>G) in the general population?

C8A p.Ile441Val (c.1321A>G) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about C8A p.Ile441Val (c.1321A>G)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

C8A p.Ile441Val

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

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

c.1321A>G · rs111937292 · VCV1434860

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type I complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -1.81	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 0.18	GERP -4.8
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	1.752	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 0.148% Middle Eastern · 9/6,062 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.011% 177/1,614,144 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
Admixed American	0.075%	1,334
Remaining individualsnot grpmax-eligible	0.0256%	3,907
African / African-American	0.024%	4,169
Finnishnot grpmax-eligible	0.0234%	4,269
European (non-Finnish)	0.0061%	16,389
South Asian	0.0022%	45,540

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: C8A
Protein: p.Ile441Val
Coding: c.1321A>G
MANE Select: NM_000562
dbSNP: rs111937292
Type: single nucleotide variant
Location: chr1:56908054 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 441: a UniProt-annotated variant site (in c8d1); the macpf domain

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type I complement component 8 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same condition
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same condition
C8A p.Lys57Thr Uncertain significance ★★ ⚠ same condition
C8A p.Pro52Leu Uncertain significance ★★ ⚠ same condition
C8A p.Ala36Glu Benign/Likely benign ★★ ⚠ same condition
C8A p.Asp202= Likely benign ★★ 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/c8a-p-ile441val (accessed [today's date]).

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