Is APLF p.Arg418Trp (c.1252C>T) pathogenic?

APLF p.Arg418Trp (c.1252C>T) is classified Uncertain significance in APLF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: ambiguous (0.3645); Ultra-rare (popmax 0.0783%, amr).

How common is APLF p.Arg418Trp (c.1252C>T) in the general population?

APLF p.Arg418Trp (c.1252C>T) is ultra-rare (popmax 0.0783%, amr) (gnomAD).

What do computational predictors say about APLF p.Arg418Trp (c.1252C>T)?

AlphaMissense predicts ambiguous (score 0.3645) — an in-silico prediction, not a clinical call.

APLF p.Arg418Trp

c.1252C>T · VCV3413592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0783%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3645	ambiguous
REVEL	0.198	benign-leaning
SaProt	LLR -17.88	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.76	GERP 2.1, phastCons 0.064
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.73 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.0783% Admixed American · 47/59,996 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.012% 194/1,613,714 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0783%	1,277
African / African-American	0.0187%	5,357
European (non-Finnish)	0.0105%	9,514
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
East Asian	0.00223%	44,864
South Asian	0.0011%	91,052

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.Arg418Trp
Coding: c.1252C>T
MANE Select: NM_173545
Type: single nucleotide variant
Location: chr2:68545278 (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.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-arg418trp (accessed [today's date]).

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