Is ROS1 p.Pro2015Thr (c.6043C>A) pathogenic?

ROS1 p.Pro2015Thr (c.6043C>A) is classified Uncertain significance in ROS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.7562); Very rare (popmax 8.48e-05%, nfe).

How common is ROS1 p.Pro2015Thr (c.6043C>A) in the general population?

ROS1 p.Pro2015Thr (c.6043C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ROS1 p.Pro2015Thr (c.6043C>A)?

AlphaMissense predicts likely pathogenic (score 0.7562) — an in-silico prediction, not a clinical call.

ROS1 p.Pro2015Thr

c.6043C>A · VCV4156180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7562 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7562	likely pathogenic
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 137 kb · p 0.12 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2021T vs ClinVar P2015T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,580 alleles

Overall 0.000657% 1/152,096 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: ROS1
Protein: p.Pro2015Thr
Coding: c.6043C>A
MANE Select: NM_001378902
Type: single nucleotide variant
Location: chr6:117317217 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.86 · 5 PDB
Residue 2015: the protein kinase domain; a β-strand

Full ROS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ROS1 c.4126+3A>G Likely benign ★★ same type
ROS1 p.Arg1500Gly Benign ★★ same type
ROS1 p.Asp1770His Benign ★★ same type
ROS1 p.Glu1896Lys Benign ★★ same type
ROS1 p.Gly1022Asp Likely benign ★★ ⚠ same type
ROS1 p.Leu1331= Benign/Likely benign ★★ same type
ROS1 p.Leu755Ile Likely benign ★★ same type
ROS1 p.Ser1298= Benign/Likely 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/ros1-p-pro2015thr (accessed [today's date]).

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