Is CFLAR p.Leu58Val (c.172C>G) pathogenic?

CFLAR p.Leu58Val (c.172C>G) is classified Uncertain significance in CFLAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely benign (0.2419); Absent from gnomAD v4.1.

How common is CFLAR p.Leu58Val (c.172C>G) in the general population?

CFLAR p.Leu58Val (c.172C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFLAR p.Leu58Val (c.172C>G)?

AlphaMissense predicts likely benign (score 0.2419) — an in-silico prediction, not a clinical call.

CFLAR p.Leu58Val

c.172C>G · VCV4653069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2419 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2419	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -10.91	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.79, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 6,236 bp · p 2.3e-12 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFLAR
Protein: p.Leu58Val
Coding: c.172C>G
MANE Select: NM_003879
Type: single nucleotide variant
Location: chr2:201130037 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.84 · 17 PDB
Residue 58: the ded 1 domain; the 'not proteolytically processed and involved in apoptosis inhibition' region; an α-helix; the 'interaction with casp8 propeptide' region; the 'interaction with fadd' region; the 'interaction with casp8' 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.Arg315Gln Uncertain significance ★ ⚠ same type
CFLAR p.Arg397Pro Uncertain significance ★ ⚠ same type
CFLAR p.Asn199Ser 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-leu58val (accessed [today's date]).

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