Is C2 p.Tyr405Ter (c.1215T>A) pathogenic?

C2 p.Tyr405Ter (c.1215T>A) is classified Pathogenic in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-01). Very rare (popmax 0.00549%, sas).

How common is C2 p.Tyr405Ter (c.1215T>A) in the general population?

C2 p.Tyr405Ter (c.1215T>A) is very rare (popmax 0.00549%, sas) (gnomAD).

C2 p.Tyr405Ter

c.1215T>A · VCV3257316

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 18
REVEL	0.237	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.2
Overall
CADD	34.0	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 0.00549% South Asian · 5/91,034 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000411% 6/1,458,300 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,207
Remaining individualsnot grpmax-eligible	0.0016%	62,360

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: C2
Protein: p.Tyr405Ter
Coding: c.1215T>A
MANE Select: NM_000063
Type: single nucleotide variant
Location: chr6:31939316 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 405: the vwfa domain; an α-helix

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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C2 p.Ala363Thr Uncertain significance ★★ ⚠ same type
C2 p.Ala682Glu Uncertain significance ★★ ⚠ same type
C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
C2 p.Arg129His Uncertain significance ★★ ⚠ same type
C2 p.Arg174Cys Uncertain significance ★★ ⚠ same type
C2 p.Arg176Cys 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/c2-p-tyr405ter (accessed [today's date]).

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