Is APLN p.Gln44Arg (c.131A>G) pathogenic?

APLN p.Gln44Arg (c.131A>G) is classified Uncertain significance in APLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1036); Very rare (popmax 0.000114%, nfe).

How common is APLN p.Gln44Arg (c.131A>G) in the general population?

APLN p.Gln44Arg (c.131A>G) is very rare (popmax 0.000114%, nfe) (gnomAD).

What do computational predictors say about APLN p.Gln44Arg (c.131A>G)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

APLN p.Gln44Arg

c.131A>G · VCV4123385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000114%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -5.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 6,001 bp · p 0.23 · regional, not allelic
Overall
CADD	19.69	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 0.000114% European (non-Finnish) · 1/877,817 alleles

Overall 0.000883% 1/113,253 alleles · very 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: APLN
Protein: p.Gln44Arg
Coding: c.131A>G
MANE Select: NM_017413
Type: single nucleotide variant
Location: chrX:129648729 (GRCh38)
Structure: AlphaFold pLDDT 67.45 · 5 PDB
Residue 44: the 'disordered' region

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

Similar variants

APLN c.67+151A>G Benign ★★ same type
APLN c.-107T>C Benign ★★ same type
APLN c.-314T>C Benign ★★ same type
APLN c.*5+62C>T Benign ★★ same type
APLN p.Arg49Trp Uncertain significance ★ ⚠ same type
APLN p.Arg59Gln Uncertain significance ★ ⚠ same type
APLN p.Arg59Trp Uncertain significance ★ ⚠ same type
APLN p.Arg63His 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/apln-p-gln44arg (accessed [today's date]).

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