Is CFLAR p.Arg303Ter (c.907C>T) pathogenic?

CFLAR p.Arg303Ter (c.907C>T) is classified Uncertain significance in CFLAR (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-17). Very rare (popmax 0.000169%, nfe).

How common is CFLAR p.Arg303Ter (c.907C>T) in the general population?

CFLAR p.Arg303Ter (c.907C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

CFLAR p.Arg303Ter

c.907C>T · VCV4959361

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 0.000169%, nfe)

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 9 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -0.25
Overall
CADD	33.0	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 0.000169% European (non-Finnish) · 2/1,180,012 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,830 alleles · very rare

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: CFLAR
Protein: p.Arg303Ter
Coding: c.907C>T
MANE Select: NM_003879
Type: single nucleotide variant
Location: chr2:201160545 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.84 · 17 PDB
Residue 303: the 'interaction with casp8 subunits p18 and p10' region; the 'caspase' region; the 'not proteolytically processed and involved in apoptosis inhibition' region; the 'interaction with casp8 propeptide' region; an α-helix; the 'interaction with traf1 and traf2' region; the 'interaction with casp3' region

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

Similar variants

CFLAR p.Leu203Ile Benign ★★ same type
CFLAR p.Val375= Benign ★★ same type
CFLAR p.Ala178Thr Uncertain significance ★ ⚠ same type
CFLAR p.Ala349Ser Uncertain significance ★ ⚠ same type
CFLAR p.Arg315Gln Uncertain significance ★ ⚠ same type
CFLAR p.Arg397Pro Uncertain significance ★ ⚠ same type
CFLAR p.Asn199Ser Uncertain significance ★ ⚠ same type
CFLAR p.Asn205His 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/cflar-p-arg303ter (accessed [today's date]).

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