Is APLF p.Arg293Lys (c.878G>A) pathogenic?

APLF p.Arg293Lys (c.878G>A) is classified Uncertain significance in APLF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00167%, amr).

How common is APLF p.Arg293Lys (c.878G>A) in the general population?

APLF p.Arg293Lys (c.878G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about APLF p.Arg293Lys (c.878G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

APLF p.Arg293Lys

c.878G>A · VCV4641641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · 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	0.0738	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -4.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -0.63, phastCons 0.94
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.73 · regional, not allelic
Overall
CADD	6.115	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 · 1/59,966 alleles

Overall 6.2e-05% 1/1,613,804 alleles · very rare exomes 1/1,461,536 · genomes 0/152,268 · joint denominator

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: APLF
Protein: p.Arg293Lys
Coding: c.878G>A
MANE Select: NM_173545
Type: single nucleotide variant
Location: chr2:68537945 (GRCh38)
Gene constraint: LOEUF 1.451 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.42 · 14 PDB
Residue 293: the 'disordered' region

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

Similar variants

APLF p.Ala17Pro Uncertain significance ★ ⚠ same type
APLF p.Ala19Thr Uncertain significance ★ ⚠ same type
APLF p.Arg10Leu Uncertain significance ★ ⚠ same type
APLF p.Arg182Lys Uncertain significance ★ ⚠ same type
APLF p.Arg418Trp Uncertain significance ★ ⚠ same type
APLF p.Arg99His Uncertain significance ★ ⚠ same type
APLF p.Arg99Leu Uncertain significance ★ ⚠ same type
APLF p.Asn161Asp 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/aplf-p-arg293lys (accessed [today's date]).

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