Is C8A c.1222+1G>A pathogenic?

C8A c.1222+1G>A is classified Likely pathogenic in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). Ultra-rare (popmax 0.0174%, afr).

How common is C8A c.1222+1G>A in the general population?

C8A c.1222+1G>A is ultra-rare (popmax 0.0174%, afr) (gnomAD).

C8A c.1222+1G>A

rs769554105 · VCV2167895

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.41	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6.4	GERP 0.097, phastCons 1
Non-coding constraint	Z -2.56	1 kb window · o/e 1.19 · regional · uncalibrated
Overall
CADD	25.1	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 0.0174% African / African-American · 13/74,900 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00105% 17/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,762
Admixed American	0.00333%	30,001
European (non-Finnish)	0.000169%	589,977

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
Coding: c.1222+1G>A
MANE Select: NM_000562
dbSNP: rs769554105
Type: single nucleotide variant
Location: chr1:56906793 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB

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

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln 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-c-1222-plus-1g-a (accessed [today's date]).

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