Is C8A p.Pro52Leu (c.155C>T) pathogenic?

C8A p.Pro52Leu (c.155C>T) is classified Uncertain significance in C8A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.112); Very rare (popmax 0.00669%, eas); Associated with type I complement component 8 deficiency.

What condition is associated with C8A p.Pro52Leu (c.155C>T)?

C8A p.Pro52Leu (c.155C>T) is associated with type I complement component 8 deficiency (ClinVar).

How common is C8A p.Pro52Leu (c.155C>T) in the general population?

C8A p.Pro52Leu (c.155C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about C8A p.Pro52Leu (c.155C>T)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

C8A p.Pro52Leu

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.155C>T · rs200247116 · VCV1982176

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type I complement component 8 deficiency

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -9.68	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 3.3	GERP 0.19, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	24.5	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 0.00669% East Asian · 3/44,862 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,613,656 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,954
African / African-American	0.00533%	18,747
Admixed American	0.00167%	59,954
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000763%	131,081

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.Pro52Leu
Coding: c.155C>T
MANE Select: NM_000562
dbSNP: rs200247116
Type: single nucleotide variant
Location: chr1:56867686 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 52: a disulfide bond; a turn; the tsp type-1 1 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.Pro52= Likely benign ★ same residue
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.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-pro52leu (accessed [today's date]).

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