Is C8A p.Arg444His (c.1331G>A) pathogenic?

C8A p.Arg444His (c.1331G>A) is classified Conflicting classifications of pathogenicity in C8A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-08). AlphaMissense: likely benign (0.1731); Rare (popmax 0.393%, nfe); Associated with type I complement component 8 deficiency.

What condition is associated with C8A p.Arg444His (c.1331G>A)?

C8A p.Arg444His (c.1331G>A) is associated with type I complement component 8 deficiency (ClinVar).

How common is C8A p.Arg444His (c.1331G>A) in the general population?

C8A p.Arg444His (c.1331G>A) is rare (popmax 0.393%, nfe) (gnomAD).

What do computational predictors say about C8A p.Arg444His (c.1331G>A)?

AlphaMissense predicts likely benign (score 0.1731) — an in-silico prediction, not a clinical call.

C8A p.Arg444His

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.1331G>A · rs143908758 · VCV789429

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1731 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.393%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type I complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.1731	likely benign
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -5.50	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.57, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	24.3	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 0.393% European (non-Finnish) · 4,635/1,180,000 alleles

Filtering AF 0.383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.379%

Overall 0.348% 5,625/1,614,134 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.539%	186
European (non-Finnish)grpmax	0.393%	255
Remaining individualsnot grpmax-eligible	0.267%	374
South Asian	0.26%	384
Admixed American	0.22%	455
African / African-American	0.128%	782
Middle Eastern	0.099%	1,010
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg444His
Coding: c.1331G>A
MANE Select: NM_000562
dbSNP: rs143908758
Type: single nucleotide variant
Location: chr1:56908064 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 444: a UniProt-annotated variant site (in c8d1); the macpf domain; an α-helix

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.Ile441Val Uncertain significance ★★ ⚠ same condition
C8A p.Lys57Thr Uncertain significance ★★ ⚠ same condition
C8A p.Pro52Leu Uncertain significance ★★ ⚠ same condition
C8A p.Ala36Glu Benign/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-arg444his (accessed [today's date]).

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