Is CABP2 p.Arg216Ter (c.646C>T) pathogenic?

CABP2 p.Arg216Ter (c.646C>T) is classified Uncertain significance in CABP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). Very rare (popmax 0.0011%, sas).

How common is CABP2 p.Arg216Ter (c.646C>T) in the general population?

CABP2 p.Arg216Ter (c.646C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

CABP2 p.Arg216Ter

c.646C>T · rs774401191 · VCV1969125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP -2.9, phastCons 1
Overall
CADD	42.0	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 0.0011% South Asian · 1/91,070 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000744% 12/1,613,850 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	0.000847%	117,999

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: CABP2
Protein: p.Arg216Ter
Coding: c.646C>T
MANE Select: NM_016366
dbSNP: rs774401191
Type: single nucleotide variant
Location: chr11:67519156 (GRCh38)
Gene constraint: LOEUF 1.299 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 68.93
Residue 216: a UniProt-annotated variant site (in dfnb93); the ef-hand 4 domain

Full CABP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CABP2 p.Arg216Gln Uncertain significance ★★ ⚠ same residue
CABP2 c.637+1G>T Pathogenic/Likely pathogenic ★★ same type
CABP2 p.Ala183Thr Uncertain significance ★★ ⚠ same type
CABP2 p.Arg101Gln Uncertain significance ★★ ⚠ same type
CABP2 p.Arg108Gln Uncertain significance ★★ ⚠ same type
CABP2 p.Arg11Gln Uncertain significance ★★ ⚠ same type
CABP2 p.Arg220Gln Uncertain significance ★★ ⚠ same type
CABP2 p.Arg73Gln 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/cabp2-p-arg216ter (accessed [today's date]).

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