Is ROCK2 p.Gln350Pro (c.1049A>C) pathogenic?

ROCK2 p.Gln350Pro (c.1049A>C) is classified Uncertain significance in ROCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely pathogenic (0.6544); Very rare (popmax 0.00535%, nfe).

How common is ROCK2 p.Gln350Pro (c.1049A>C) in the general population?

ROCK2 p.Gln350Pro (c.1049A>C) is very rare (popmax 0.00535%, nfe) (gnomAD).

What do computational predictors say about ROCK2 p.Gln350Pro (c.1049A>C)?

AlphaMissense predicts likely pathogenic (score 0.6544) — an in-silico prediction, not a clinical call.

ROCK2 p.Gln350Pro

c.1049A>C · VCV3790139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6544 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6544	likely pathogenic
REVEL	0.316	indeterminate
SaProt	LLR -12.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP -0.63, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 123 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	25.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% European (non-Finnish) · 63/1,178,010 alleles

Filtering AF 0.00427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00403% 65/1,611,306 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00535%	18,699
Remaining individualsnot grpmax-eligible	0.0016%	62,336
African / African-American	0.00134%	74,896

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: ROCK2
Protein: p.Gln350Pro
Coding: c.1049A>C
MANE Select: NM_004850
Type: single nucleotide variant
Location: chr2:11222133 (GRCh38)
Gene constraint: LOEUF 0.346 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.79 · 23 PDB
Residue 350: the protein kinase domain

Full ROCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ROCK2 c.3609-11A>C Benign ★★ same type
ROCK2 p.Thr431Asn Benign ★★ same type
ROCK2 p.Ala1013Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala1018Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala663Thr Uncertain significance ★ ⚠ same type
ROCK2 p.Ala663Val Uncertain significance ★ ⚠ same type
ROCK2 p.Arg1044Ter Uncertain significance ★ same type
ROCK2 p.Arg1050His 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/rock2-p-gln350pro (accessed [today's date]).

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