Is APLF p.Pro9Ser (c.25C>T) pathogenic?

APLF p.Pro9Ser (c.25C>T) is classified Uncertain significance in APLF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). AlphaMissense: ambiguous (0.442); Very rare (popmax 0.000101%, nfe).

How common is APLF p.Pro9Ser (c.25C>T) in the general population?

APLF p.Pro9Ser (c.25C>T) is very rare (popmax 0.000101%, nfe) (gnomAD).

What do computational predictors say about APLF p.Pro9Ser (c.25C>T)?

AlphaMissense predicts ambiguous (score 0.442) — an in-silico prediction, not a clinical call.

APLF p.Pro9Ser

c.25C>T · VCV3306587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000101%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.442	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -6.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.73 · regional, not allelic
Overall
CADD	23.5	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 0.000101% European (non-Finnish) · 1/988,046 alleles

Overall 8.1e-05% 1/1,234,818 alleles · very rare exomes 1/1,082,508 · genomes 0/152,310 · 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.Pro9Ser
Coding: c.25C>T
MANE Select: NM_173545
Type: single nucleotide variant
Location: chr2:68467756 (GRCh38)
Gene constraint: LOEUF 1.451 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.42 · 14 PDB
Residue 9: the fha-like domain; a β-strand

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-pro9ser (accessed [today's date]).

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