Is CFLAR p.Arg315Gln (c.944G>A) pathogenic?

CFLAR p.Arg315Gln (c.944G>A) is classified Uncertain significance in CFLAR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely benign (0.1592); Very rare (popmax 0.00167%, amr).

How common is CFLAR p.Arg315Gln (c.944G>A) in the general population?

CFLAR p.Arg315Gln (c.944G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CFLAR p.Arg315Gln (c.944G>A)?

AlphaMissense predicts likely benign (score 0.1592) — an in-silico prediction, not a clinical call.

CFLAR p.Arg315Gln

c.944G>A · rs778008665 · VCV2268192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1592	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.001, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 28 kb · p 5.8e-05 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,984 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed Americangrpmax	0.00167%	59,984
African / African-American	0.00134%	74,832
European (non-Finnish)	0.0011%	90,770

Ashkenazi Jewish 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: CFLAR
Protein: p.Arg315Gln
Coding: c.944G>A
MANE Select: NM_003879
dbSNP: rs778008665
Type: single nucleotide variant
Location: chr2:201160582 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.84 · 17 PDB
Residue 315: the 'interaction with casp8 subunits p18 and p10' region; the 'caspase' region; the 'not proteolytically processed and involved in apoptosis inhibition' region; a β-strand; 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.Arg303Ter 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-arg315gln (accessed [today's date]).

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