Is C8A p.Ser445del (c.1334_1336del) pathogenic?

C8A p.Ser445del (c.13341336del) is classified Uncertain significance in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Very rare (popmax 0.00329%, sas).

How common is C8A p.Ser445del (c.1334_1336del) in the general population?

C8A p.Ser445del (c.1334_1336del) is very rare (popmax 0.00329%, sas) (gnomAD).

C8A p.Ser445del

c.1334_1336del · rs1386656012 · VCV1441562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.87	GERP -4.9, phastCons 0.004

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00103% 15/1,461,860 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
South Asiangrpmax	0.00329%	30,360
European (non-Finnish)	0.000763%	131,112

Remaining individuals 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.Ser445del
Coding: c.1334_1336del
MANE Select: NM_000562
dbSNP: rs1386656012
Type: Deletion
Location: chr1:56908066 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 445: 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

Similar variants

C8A c.655-4del Benign ★★ same type
C8A p.Ala153fs Pathogenic ★ same type
C8A p.Ala360fs Pathogenic ★ same type
C8A p.Cys194fs Pathogenic ★ same type
C8A p.Thr72fs Pathogenic ★ same type
C8A p.Val240_Lys241del Uncertain significance ★ same type

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-ser445del (accessed [today's date]).

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