Is APLF p.Ser149Ile (c.446G>T) pathogenic?

APLF p.Ser149Ile (c.446G>T) is classified Uncertain significance in APLF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.00402%, afr).

How common is APLF p.Ser149Ile (c.446G>T) in the general population?

APLF p.Ser149Ile (c.446G>T) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about APLF p.Ser149Ile (c.446G>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

APLF p.Ser149Ile

c.446G>T · rs964128558 · VCV3127833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -7.18	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 2.4	GERP -0.15, phastCons 0.98
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.73 · regional, not allelic
Overall
CADD	18.01	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 0.00402% African / African-American · 3/74,714 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00211% 34/1,610,806 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,905
European (non-Finnish)	0.00255%	39,279
Remaining individualsnot grpmax-eligible	0.00161%	62,274

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.Ser149Ile
Coding: c.446G>T
MANE Select: NM_173545
dbSNP: rs964128558
Type: single nucleotide variant
Location: chr2:68513184 (GRCh38)
Gene constraint: LOEUF 1.451 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.42 · 14 PDB
Residue 149: a modified residue (phosphoserine)

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-ser149ile (accessed [today's date]).

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