Is APLF p.Cys427Arg (c.1279T>C) pathogenic?

APLF p.Cys427Arg (c.1279T>C) is classified Uncertain significance in APLF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.9887); Ultra-rare (popmax 0.0333%, afr).

How common is APLF p.Cys427Arg (c.1279T>C) in the general population?

APLF p.Cys427Arg (c.1279T>C) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about APLF p.Cys427Arg (c.1279T>C)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

APLF p.Cys427Arg

c.1279T>C · rs116704384 · VCV2267185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic · top 1% in APLF
REVEL	0.679	pathogenic-leaning
SaProt	LLR -16.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.73 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0333% African / African-American · 25/75,018 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00155% 25/1,612,980 alleles · ultra-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: APLF
Protein: p.Cys427Arg
Coding: c.1279T>C
MANE Select: NM_173545
dbSNP: rs116704384
Type: single nucleotide variant
Location: chr2:68545305 (GRCh38)
Gene constraint: LOEUF 1.451 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.42 · 14 PDB

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.Arg293Lys 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

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-cys427arg (accessed [today's date]).

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