Is APLN p.Arg59Gln (c.176G>A) pathogenic?

APLN p.Arg59Gln (c.176G>A) is classified Uncertain significance in APLN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). AlphaMissense: likely benign (0.1827); Very rare (popmax 0.00938%, amr).

How common is APLN p.Arg59Gln (c.176G>A) in the general population?

APLN p.Arg59Gln (c.176G>A) is very rare (popmax 0.00938%, amr) (gnomAD).

What do computational predictors say about APLN p.Arg59Gln (c.176G>A)?

AlphaMissense predicts likely benign (score 0.1827) — an in-silico prediction, not a clinical call.

APLN p.Arg59Gln

c.176G>A · rs377120516 · VCV3127838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00938%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1827	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -7.56	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 5.9	GERP 0.86, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 6,001 bp · p 0.23 · regional, not allelic
Overall
CADD	23.8	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 0.00938% Admixed American · 4/42,659 alleles

Filtering AF 0.00319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00187%

Overall 0.00278% 33/1,186,636 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00938%	10,665
East Asian	0.00618%	16,189
African / African-American	0.00525%	19,030
Remaining individualsnot grpmax-eligible	0.00429%	23,316
European (non-Finnish)	0.00249%	40,125

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.Arg59Gln
Coding: c.176G>A
MANE Select: NM_017413
dbSNP: rs377120516
Type: single nucleotide variant
Location: chrX:129648684 (GRCh38)
Structure: AlphaFold pLDDT 67.45 · 5 PDB
Residue 59: the 'disordered' region

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

Similar variants

APLN p.Arg59Trp Uncertain significance ★ ⚠ same residue
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.Arg63His Uncertain significance ★ ⚠ same type
APLN p.Arg68Cys 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-arg59gln (accessed [today's date]).

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