Is C8A p.Thr72fs (c.213_219del) pathogenic?

C8A p.Thr72fs (c.213219del) is classified Pathogenic in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). Very rare (popmax 0.00834%, amr).

How common is C8A p.Thr72fs (c.213_219del) in the general population?

C8A p.Thr72fs (c.213_219del) is very rare (popmax 0.00834%, amr) (gnomAD).

C8A p.Thr72fs

c.213_219del · rs1259084585 · VCV1064346

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 2.3, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,966 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000372% 6/1,613,610 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,993
African / African-American	0.00134%	74,906

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.Thr72fs
Coding: c.213_219del
MANE Select: NM_000562
dbSNP: rs1259084585
Type: Deletion
Location: chr1:56874990 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 72: a disulfide bond; an α-helix; the tsp type-1 1 domain

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.Ser445del Uncertain significance ★ 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-thr72fs (accessed [today's date]).

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