Is AXL p.Arg48Pro (c.143G>C) pathogenic?

AXL p.Arg48Pro (c.143G>C) is classified Uncertain significance in AXL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: likely benign (0.1498); Very rare (popmax 8.48e-05%, nfe).

How common is AXL p.Arg48Pro (c.143G>C) in the general population?

AXL p.Arg48Pro (c.143G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about AXL p.Arg48Pro (c.143G>C)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

AXL p.Arg48Pro

c.143G>C · rs200598880 · VCV2255554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -5.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,399 bp · p 0.43 · regional, not allelic
Overall
CADD	27.6	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 8.48e-05% European (non-Finnish) · 1/1,179,062 alleles

Overall 6.2e-05% 1/1,611,924 alleles · very rare exomes 1/1,459,654 · genomes 0/152,270 · 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: AXL
Protein: p.Arg48Pro
Coding: c.143G>C
MANE Select: NM_021913
dbSNP: rs200598880
Type: single nucleotide variant
Location: chr19:41220693 (GRCh38)
Gene constraint: LOEUF 0.625 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.57 · 4 PDB
Residue 48: the 'interaction with gas6' region; the ig-like c2-type 1 domain

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

Similar variants

AXL p.Arg48Trp Uncertain significance ★ ⚠ same residue
AXL p.Arg217His Uncertain significance ★★ ⚠ same type
AXL p.Glu818Lys Uncertain significance ★★ same type
AXL p.Pro833Arg Uncertain significance ★★ ⚠ same type
AXL c.1135-238C>T Benign ★★ same type
AXL c.1285+62C>G Benign ★★ same type
AXL c.1286-159G>A Benign ★★ same type
AXL c.1286-185C>T Benign ★★ 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/axl-p-arg48pro (accessed [today's date]).

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