Is AXL p.Pro614Ser (c.1840C>T) pathogenic?

AXL p.Pro614Ser (c.1840C>T) is classified Uncertain significance in AXL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely pathogenic (0.7141); Very rare (popmax 0.00267%, afr).

How common is AXL p.Pro614Ser (c.1840C>T) in the general population?

AXL p.Pro614Ser (c.1840C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about AXL p.Pro614Ser (c.1840C>T)?

AlphaMissense predicts likely pathogenic (score 0.7141) — an in-silico prediction, not a clinical call.

AXL p.Pro614Ser

c.1840C>T · rs140047155 · VCV2792960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7141	likely pathogenic
REVEL	0.288	benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 0.81, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 21 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	22.7	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 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,990 alleles · very rare exomes 0/1,461,864 · genomes 2/152,126 · 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.Pro614Ser
Coding: c.1840C>T
MANE Select: NM_021913
dbSNP: rs140047155
Type: single nucleotide variant
Location: chr19:41252881 (GRCh38)
Gene constraint: LOEUF 0.625 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.57 · 4 PDB
Residue 614: the protein kinase domain

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

Similar variants

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
AXL c.1286-59G>A 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-pro614ser (accessed [today's date]).

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