Is VCL p.Arg449Ter (c.1345C>T) pathogenic?

VCL p.Arg449Ter (c.1345C>T) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-09). Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Arg449Ter (c.1345C>T)?

VCL p.Arg449Ter (c.1345C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Arg449Ter (c.1345C>T) in the general population?

VCL p.Arg449Ter (c.1345C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

VCL p.Arg449Ter

c.1345C>T · rs1173871364 · VCV1770461

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 0.00133%, afr)

Conditions

Cardiovascular phenotype

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 in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 10 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.68, phastCons 0.99
Overall
CADD	39.0	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 0.00133% African / African-American · 1/75,054 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000496% 8/1,614,130 alleles · very rare exomes 7/1,461,822 · genomes 1/152,308 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,030
African / African-Americangrpmax	0.00133%	75,054
South Asian	0.0011%	91,086
European (non-Finnish)	0.000424%	236,000

Finnish 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: VCL
Protein: p.Arg449Ter
Coding: c.1345C>T
MANE Select: NM_014000
dbSNP: rs1173871364
Type: single nucleotide variant
Location: chr10:74090191 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 449: the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' region; a turn

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VCL p.Arg449Gln Uncertain significance ★★ same residue
VCL p.Arg449= Likely benign ★★ same residue
VCL c.1352+5G>A Uncertain significance ★★ same condition
VCL c.1543+4A>G Uncertain significance ★★ same condition
VCL c.2132-3C>A Uncertain significance ★★ same condition
VCL c.239+3G>A Uncertain significance ★★ same condition
VCL p.Ala1023Thr Uncertain significance ★★ ⚠ same condition
VCL p.Ala1120Thr Uncertain significance ★★ ⚠ same condition

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/vcl-p-arg449ter (accessed [today's date]).

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